Methods for treating hepatitis C

ABSTRACT

In accordance with the present invention, compounds that inhibit viral replication, preferably Hepatitis C Virus (HCV) replication, have been identified, and methods for their use provided. In one aspect of the invention, compounds useful in the treatment or prevention of a viral infection are provided. In another aspect of the invention, compounds useful in the treatment or prevention of HCV infection are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of each of U.S. ProvisionalApplication No. 60/587,487, filed Jul. 14, 2004, U.S. ProvisionalApplication No. 60/634,979, filed Dec. 13, 2004, U.S. ProvisionalApplication No. 60/645,586, filed Jan. 24, 2005, U.S. ProvisionalApplication No. 60/665,349, filed Mar. 28, 2005, and U.S. ProvisionalApplication No. 60/675,440, filed Apr. 28, 2005, all of whichapplications are incorporated herein by reference in their entireties.This application corresponds to International ApplicationPCT/US2005/024881, filed Jul. 14, 2005, which application is hereinincorporated by reference in its entirety.

GOVERNMENT SUPPORT

The present invention was made with U.S. Government support under DHHSGrant No. 5R44 AI054029-03. The U.S. Government has certain rights inthe invention.

FIELD OF THE INVENTION

The present invention relates to methods for treating Hepatitis C usingIndole compounds that modify translational control of Hepatitis C virus.

BACKGROUND OF THE INVENTION

An estimated 170 million people worldwide are reported to be infectedwith hepatitis C virus (HCV), the causative agent of hepatitis C.Seventy to eighty percent of HCV infections lead to chronic liverinfection, which in turn may result in severe liver disease, includingliver fibrosis, cirrhosis, and hepatocellular carcinoma (115).

HCV constitutes the Hepacivirus genus of the family Flaviviridae (106),and contains a positive-stranded 9.6 kb RNA genome. The features of theHCV genome include a 5′-untranslated region (UTR) that encodes aninternal ribosome entry site (IRES) that directs the translation of asingle long open reading frame (ORF) encoding a polyprotein of 3,010amino acids. The HCV ORF is followed by a 3′-UTR of variable length,depending on the HCV variant, that encodes the sequences required forthe initiation of antigenomic strand synthesis (79).

The HCV IRES and 3′-UTR both encode regions of RNA structures that arerequired for genome translation and replication. The HCV polyprotein isposttranslationally processed into at least 10 mature viral proteins,including the structural proteins core (putative nucleocapsid), E1 andE2 and the nonstructural (NS) proteins NS2 to NS5B.

Three distinct elements have been shown to be involved in HCVIRES-mediated translation: (1) integrity of the global structure of HCVIRES, (2) the 3′-terminal region of the HCV genome; and (3) trans-actingcellular factors that interact with the HCV IRES element and assist intranslation initiation (35).

The initiation of protein synthesis in eukaryotic cells predominantlyfollows the 5′ cap-dependent, first AUG rule (61). However, anincreasing number of viral (6, 12, 28, 31a, 50, 95, 97, 98, 105, 128)and cellular mRNAs (18, 39, 45, 78, 91, 130) have been shown to use anIRES element to direct translation initiation. In 1992, an IRES elementwas reported in the 5′ UTR of the HCV RNA genome (129), indicating thatsynthesis of the viral protein is initiated in a cap-independentfashion.

A bicistronic expression system can be used to define and evaluate thefunction of IRES elements. This test system harbors two differentreporter genes in which the 5′-proximal reporter gene is expressed by acap dependent translation mechanism while the second reporter isexpressed only if an upstream sequence inserted in the intergenic spacecontains an IRES sequence element. Using this system, a putative IRES inthe HCV 5′ UTR was unambiguously demonstrated to function as an IRESinvolved in translational control of viral proteins (133). In vitrotranslation, RNA transfection, and mutagenesis studies provided furtherevidence that the HCV 5′ UTR contains an IRES element (23, 41, 42, 108,129, 132, 133, 134). Both in vitro and cell-based studies demonstratedthat the HCV IRES guides cellular translation initiation factors to aninternal site of the viral RNA (56, 58, 120), thus functionallydemonstrating the HCV IRES activity. Taken together, these resultsdemonstrate that the HCV 5′-UTR contains an IRES element that plays anactive and crucial role in the mechanism of internal initiation for HCVprotein translation.

The IRES is one of the most conserved regions of the HCV genome,reflecting its essential nature for viral replication and proteinsynthesis (13, 118, 122). Although both 5′ and 3′ sequences of the IRESappear to play a role in the control of initiation of translation (42,109, 110, 113, 136), the minimal sequence requirement for HCV IRESfunction has been mapped to a region between nucleotides 44-354 (40).

Biochemical probing and computer modeling indicate that the HCV IRES andits 5′ sequence is folded into a distinct structure that consists offour major domains and a pseudoknot (11, 42, 122). Domain I contains asmall stem-loop structure that does not appear to be a functional partof the IRES element while domains II, III, and IV contain the HCV IRESactivity (43, 111). The relationships between secondary and tertiarystructures of the HCV IRES and their function have recently beenestablished (5, 55, 56, 99, 124). Both domains II and III consist ofmultiple stems, loops, and bulges and are important for IRES activity(23, 40, 51, 52, 54, 56, 64, 74, 75, 93, 107, 108, 110, 124, 127, 131,139). Domain II can induce conformational changes on the ribosome thathave been implicated in the decoding process (124). Domain III has thehighest degree of structural conservation among the different HCVstrains. It comprises the core of the flavivirus IRES and has 6subdomains (40). Various studies have shown that subdomain IIId formscomplex secondary/tertiary structures and is critical for initiationactivity (55, 56, 57, 124, 129). Domain IV has one stem-loop that spansthe initiation codon and is specific for the HCV IRES (41, 122), but theprecise role of domain IV in IRES activity remains controversial (41,112).

The role of the HCV IRES is to position the translational machinery nearan internal initiator codon in the viral mRNA. The translationinitiation mechanism of the HCV IRES differs significantly from that of5′-cap-dependent translation initiation (7, 21, 31, 35, 81, 96, 114,123). Most cellular capped mRNAs utilize a number of initiation factors(eIFs) that are required for the translation initiation process. Theinitial steps of the process require proteins that interact with the 5′cap structure and recruit the 40S ribosomal subunit to the cap-proximalregion of mRNA. This complex then scans 3′ of the cap, until reaching anAUG codon at which translation will initiate (21, 114). However, in thecase of HCV, the IRES functionally replaces the 5′ cap structure,allowing the 40S ribosomal subunit and eIF3 to bind directly to the RNA.Subdomain IIId of the HCV IRES harbors the binding site for the 40Sribosomal subunit and the only initiation factors required fortranslation initiation are eIF2, eIF3, and eIF4E (15, 58, 94, 100, 120,124).

The polypyrimidine track-binding protein (PTB) and La autoantigen arenoncanonical translation initiation factors that bind to and enhance HCVIRES activity (1, 2, 3, 4, 5, 30, 48, 49, 53). PTB, a 57-kDa proteininvolved in RNA splicing, is also necessary for efficient IRES-mediatedtranslation initiation of picornavirus mRNA, and some cellular mRNAs(10, 11, 36, 53, 59, 89, 92). The La autoantigen, a 52 kDadouble-stranded RNA unwinding protein, also increases the activity ofpoliovirus and cellular IRESs (38, 85, 86). Other cellular factorsinvolved in HCV IRES-mediated translation initiation include proteasomeα-subunit PSMA7 (62), ribosomal protein S5 (26), ribosomal protein S9(24, 25, 100), and hnRNPL (33). However, the role of these RNA-bindingproteins in HCV IRES-mediated initiation of translation is unclear.Recently, it was reported that the activity of interferon (IFN) αagainst HCV replication might target HCV IRES-mediated translationinitiation by causing a reduction of La protein levels (117). Thus, aninhibitor that blocks interaction between the IRES and the noncanonicalfactors might efficiently inhibit HCV replication and lack cytotoxicity.

Currently, only interferon (IFN) α and the nucleoside analogueribavirin, in combination, are marketed for the treatment of HCVinfection. However, these two agents are immunomodulators and havelimited efficacy, relatively high toxicity, and high cost (80, 83, 84,138). Although the treatment outcome is variable among the six major HCVgenotypes, only about one-half of all treated patients respond totherapy, suggesting that the virus encodes protein products that maydirectly or indirectly attenuate the antiviral action of IFN. IFNs arenaturally produced in response to virus infection, and cellular exposureto IFN leads to the induced expression of a variety of IFN-stimulatedgenes (ISGs), many of which have an antiviral function. ISG action canlimit virus replication at multiple points within the replicative cycle.

There remains a need for a more effective means of treating patientsafflicted with HCV. Specifically, a need exists for novel antiviraldrugs that have no cross-resistance with existing treatment modalities,and which demonstrate synergy with other anti-HCV agents. The applicantsset out to identify drug candidates that inhibit HCV infection and weresuccessful in identifying Indole compounds that are useful as anti-HCVagents. Without being limited to one theory, it is believed that thecompounds of the present invention inhibit IRES-mediated initiation,elongation, and termination, i.e. translation.

The compounds of the present invention are also useful for inhibitingtranslation of other cap-independent viruses that contain an IRESelement. Such viruses include those of the picornavirus genus, such aspoliovirus, hepatitis A virus and rhinovirus; those of the coronavirusgenus, such as SARS; those of the arbovirus genus; those of theflavivirus genus, such as yellow fever, dengue, and West Nile virus,herpesviruses, such as herpes simplex virus and Kaposi'ssarcoma-associated herpesvirus, or any other virus with a similar modeof replication. Furthermore, compounds of the invention are also usefulfor inhibiting HIV, or any other virus with a similar mode oftranslation.

All documents referred to herein are incorporated by reference into thepresent application as though fully set forth herein.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds that can inhibit HCVreplication have been identified. Also in accordance with the presentinvention, compounds that can inhibit HCV infection have beenidentified, and methods for their use provided.

In one aspect of the invention, compounds of Formula (I) are providedwhich are useful in the prevention and/or treatment of HCV infection.Without being limited to one theory, it is believed that the compoundsof the present invention inhibit IRES-mediated initiation, elongationand termination, i.e., translation. The compounds of Formula (I) mayalso be useful for inhibiting and/or treating other viral infectionswhere the virus contains an IRES element. Such viruses include those ofthe picornavirus genus, such as by way of non-limiting examplepoliovirus, hepatitis A virus and rhinovirus; those of the coronaviridaegenus, such as by way of non-limiting example SARS; those of thearbovirus genus; those of the flavivirus genus, such as by way ofnon-limiting example yellow fever, dengue, and West Nile virus;herpesviruses, such as by way of non-limiting example herpes simplexvirus and Kaposi's sarcoma-associated herpesvirus, or any other viruswith a similar mode of replication. Furthermore, compounds of theinvention are also useful for inhibiting HIV, or any other virus with asimilar mode of translation.

In another aspect of the invention, methods are provided for theprevention and/or treatment of HCV infection.

In yet another aspect of the invention, pharmaceutical compositionscomprising the compounds of the invention for the prevention and/ortreatment of HCV infection are provided.

In one embodiment, the invention is directed to methods for inhibitingHCV IRES-mediated initiation and translation comprising administering anamount of one or more compound of the invention, effective forinhibiting IRES-mediated initiation and translation, to a subject inneed thereof.

CERTAIN EMBODIMENTS Embodiment 1

A pharmaceutical composition for the prevention or treatment ofHepatitis C viral (HCV) infection comprising a therapeutically effectiveamount of at least one compound having the following formula:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc) group, where R_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,        -   a

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   —CH₂OCOR_(x), and R_(x) is as defined above;        or a pharmaceutically acceptable salt thereof, a        pharmaceutically acceptable excipient, and optionally at least        one additional anti-HCV agents.

Embodiment 2

The pharmaceutical composition of Embodiment 1, wherein said optional atleast one additional anti-HCV agent is selected from the groupconsisting of pegylated interferon, un-pegylated interferon, ribavirinor prodrugs or derivatives thereof, a glucosidase inhibitor, a proteaseinhibitor, a polymerase inhibitor, p7 inhibitors, an entry inhibitor, afusion inhibitor, an anti-fibrotic, a caspase inhibitor, a drug whichtargets inosine monophosphate dehydrogenase inhibitors (IMPDH),synthetic thymosin alpha 1, therapeutic vaccines, immunomodulators, aglycosidase inhibitor, a helicase inhibitor, a Toll-like receptoragonist, and combinations thereof.

Embodiment 3

The pharmaceutical composition of Embodiment 1, wherein X is selectedfrom the group consisting of —hydrogen; —a cyano group; and —a —COR_(a)group, where R_(a) is: —a C₁ to C₆ alkyl, or —a dialkyl-amino.

Embodiment 4

The pharmaceutical composition of Embodiment 1, wherein Y is selectedfrom the group consisting of

Embodiment 5

The pharmaceutical composition of Embodiment 1, wherein Y is selectedfrom the group consisting of

Embodiment 6

The pharmaceutical composition of Embodiment 1, wherein R is a hydrogen.

Embodiment 7

The pharmaceutical composition of Embodiment 1, wherein R₁ is selectedfrom the group consisting of a hydrogen, a nitro group, or an alkoxy.

Embodiment 8

The pharmaceutical composition of Embodiment 1, wherein R₂ is selectedfrom the group consisting of a hydroxy, a hydrogen, a haloalkyl group, anitro group, an amide, —COOR_(x) or an alkoxy.

Embodiment 9

The pharmaceutical composition of Embodiment 1, wherein R₃ is ahydrogen.

Embodiment 10

The pharmaceutical composition of Embodiment 1, wherein said compound isselected from the compounds of Table A.

Embodiment 11

The pharmaceutical composition of Embodiment 1 wherein said compound isselected from the compounds of Table B or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable excipient.

Embodiment 12

The pharmaceutical composition of Embodiment 17, wherein saidcomposition further comprises at least one additional anti-HCV agentselected from the group consisting of pegylated interferon, un-pegylatedinterferon, ribavirin or prodrugs or derivatives thereof, a glucosidaseinhibitor, a protease inhibitor, a polymerase inhibitor, p7 inhibitors,an entry inhibitor, a fusion inhibitor, an anti-fibrotic, a caspaseinhibitor, a drug which targets inosine monophosphate dehydrogenaseinhibitors (IMPDH), synthetic thymosin alpha 1, therapeutic vaccines,immunomodulators, a glycosidase inhibitor, a helicase inhibitor, aToll-like receptor agonist, and combinations thereof.

Embodiment 13

A method for treating a subject for a Hepatitis C viral (HCV) infectioncomprising administering to said subject a pharmaceutical compositioncomprising an HCV inhibitory amount of at least one compound having thefollowing formula:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc) group, where R_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   —CH₂OCOR_(x), and R_(x) is as defined above;        or a pharmaceutically acceptable salt thereof and a        pharamceutically acceptable excipient.

Embodiment 14

The method of Embodiment 13, wherein said pharmaceutical compositionfurther comprises at least one additional anti-HCV agent.

Embodiment 15

The method of Embodiment 14, wherein said at least one additionalanti-HCV agent is selected from the group consisting of pegylatedinterferon, un-pegylated interferon, ribavirin or prodrugs orderivatives thereof, a glucosidase inhibitor, a protease inhibitor, apolymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusioninhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targetsinosine monophosphate dehydrogenase inhibitors (IMPDH), syntheticthymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidaseinhibitor, a helicase inhibitor, a Toll-like receptor agonist, andcombinations thereof.

Embodiment 16

The method of Embodiment 13, wherein X is selected from the groupconsisting of —hydrogen; —a cyano group; and —a —COR_(a) group, whereR_(a) is: -a C₁ to C₆ alkyl, or —a dialkyl-amino.

Embodiment 17

The method of Embodiment 13, wherein Y is selected from the groupconsisting of

Embodiment 18

The method of Embodiment 13, wherein Y is selected from the groupconsisting of

Embodiment 19

The method of Embodiment 13, wherein R is a hydrogen.

Embodiment 20

The method of Embodiment 13, wherein R₁ is selected from the groupconsisting of a hydrogen; —a halogen; —a nitro group; —a 5 or 6 memberedheterocycle; —an alkoxy optionally substituted with: —a C₆ to C₈ aryl;-a C₆ to C₈ aryl optionally substituted with an alkoxy

Embodiment 21

The method of Embodiment 13, wherein R₂ is selected from the groupconsisting of —a nitro group; —a hydrogen; —a halogen; —a hydroxy group;—a C₁ to C₆ alkyl group, optionally substituted with one or morehalogens; —an alkoxy group optionally substituted with: —one or morehalogens, —an —OCOR_(x) group, where R_(x) is as defined above, —adialkyl-amino optionally substituted with an alkoxy, —a 5 or 6 memberedheterocycle group optionally substituted with a C₁ to C₆ alkyl, or —a 5or 6 membered heteroaryl group; —an amide group; and —a —NHSO₂R_(x)group, where R_(x) is as defined above

Embodiment 22

The method of Embodiment 13, wherein R₃ is a hydrogen.

Embodiment 23

The method of Embodiment 13, wherein said compound is selected from thecompounds of Table A.

Embodiment 24

The method of Embodiment 13, wherein said compound is selected from thecompounds of Table B.

Embodiment 25

A method for treating or preventing infection by a virus in a subject,wherein said virus comprises a internal ribosome entry site (IRES),comprising administering to said subject a pharmaceutical compositioncomprising a viral inhibitory amount of one or more compound having thefollowing formula:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R₁ is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc) group, where R_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C 6 alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   —CH₂OCOR_(x), and R_(x) is as defined above;        and/or a pharmaceutically acceptable salt thereof, together with        a pharmaceutically acceptable excipient.

Embodiment 33

The method of Embodiment 32 wherein said pharmaceutical compositionfurther comprises at least one additional anti-viral agent.

Embodiment 34

The method of Embodiment 33, wherein said at least one additionalanti-viral agent is elected from the group consisting of pegylatedinterferon, un-pegylated interferon, ribavirin or prodrugs orderivatives thereof, a glucosidase inhibitor, a protease inhibitor, apolymerase inhibitor, p7 inhibitors, an entry inhibitor, a fusioninhibitor, an anti-fibrotic, a caspase inhibitor, a drug which targetsinosine monophosphate dehydrogenase inhibitors (IMPDH), syntheticthymosin alpha 1, therapeutic vaccines, immunomodulators, a glycosidaseinhibitor, a helicase inhibitor, and a Toll-like receptor agonist.

Embodiment 26

A compound selected from the group consisting of the following:

Embodiment 27

A compound selected from the group consisting of the following:

Embodiment 27

A compound selected from the group consisting of the following:

Embodiment 29

A pharmaceutical composition for affecting viral IRES activity in asubject infected with a virus, comprising one or more compound havingthe following formula:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C, to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc group, where R) _(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   where the alkyls are optionally substituted with a                    halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C 6 alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   CH₂OCOR_(x), and R_(x) is as defined above;        or a pharmaceutically acceptable salt thereof, a        pharmaceutically acceptable excipient, and optionally one or        more compound known in the art to affect IRES activity.

Embodiment 30

The pharmaceutical composition of Embodiment 29, wherein said one ormore compound known in the art to affect IRES activity affects IRESmediated translation of the single ORF encoding the polyprotein.

Embodiment 31

A method for affecting viral IRES activity in a subject infected with avirus, comprising administering to said subject one or more compoundhaving the following formula:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   -    or

        -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,

        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    group, where W_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or    -   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   CH₂OCOR_(x), and R_(x) is as defined above;        or a pharmaceutically acceptable salt thereof, and a        pharmaceutically acceptable excipient and optionally one or more        compound known in the art to affect IRES activity.

Embodiment 32

The method of Embodiment 31, wherein said compound known in the art toaffect IRES activity affects IRES mediated translation of the single ORFencoding the polyprotein.

Embodiment 33

A pharmaceutical composition for affecting viral IRES activity in asubject infected with a virus, comprising one or more compound havingthe following formula, in an amount effective for affecting viral IRESactivity:

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;    -   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

-   -    where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

-   -    where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as        defined above, or an —SO₂R_(x), where R_(x) is as defined above;        or

-   -    where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;    -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -   where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc) group, where R_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or-   —CH₂OCOR_(x), and R_(x) is as defined above;-   or a pharmaceutically acceptable salt thereof and a pharmaceutically    acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the HCV-PV chimera construct. The cloverleaf-like RNAstructure of PV, an essential cis-acting replication signal ending withthe genome-linked protein VPg, is located at the 5′ end of the genome.The solid (HCV) and open (PV) boxes depict open reading frames encodingviral polypeptides. The position of the HCV core fragment (the first 123amino acids) gene is denoted by A Core. Overall, the HCV_specificsequence in the HCV-PV spans from nucleotides 18 to 710 (139).

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds that modify HCVtranslation have been identified and methods of using these compoundsfor preventing or treating HCV infection are provided. Without beinglimited to one theory, it is believed that the compounds of the presentinvention inhibit IRES-mediated initiation and translation. The HCV IRESdirects the translation of a single long ORF encoding a polyprotein thatis posttranslationally processed into at least 10 mature viral proteins,including the structural proteins core (putative nucleocapsid), E1 andE2 and the nonstructural (NS) proteins NS2 to NS5B.

A. Compounds of the Invention

In one aspect of the invention, compounds of the invention are providedwhich are useful for preventing or treating HCV infection.

Preferred compounds of the present invention useful for preventing ortreating HCV infection include those of Formula (I) as shown below.

wherein:

-   X is:    -   hydrogen;    -   a nitro group;    -   a cyano group;    -   a —COR_(a) group, where R_(a) is:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or a            halogen, or        -   a dialkyl-amino;    -   a —COOR_(x) group, where R_(x) is a C₁ to C₆ alkyl;    -   a formyl group;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy; or    -   a 5 or 6-membered heteroaryl optionally substituted with:        -   a C₁ to C₆ alkyl,        -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one            or more halogens, or        -   a 5 to 6 membered heteroaryl;-   Y is:    -   a hydrogen;    -   a haloalkyl;    -   a halogen;    -   an amino optionally substituted with one or more C₁ to C₆        alkyls;    -   a benzofuran;    -   a benzothiophene;    -   a dibenzofuran;    -   a dibenzothiophene;    -   a benzothiazole;    -   a naphthalene;    -   an indole, optionally substituted on the nitrogen with a C₁ to        C₆ alkyl;

where R_(b) is a hydrogen or a C₁ to C₆ alkyl, and n is 0 or 1;

where R_(c) is a hydrogen, a —CONHR_(x), where R_(x) is as definedabove, or an —SO₂R_(x), where R_(x) is as defined above; or

where R_(d) is a C₁ to C₆ alkyl or a C₆ to C₈ aryl;

-   -   a —NHCOR_(e) group, where R_(e) is:        -   a C₁ to C₆ alkyl;        -   a C₆ to C₈ aryl optionally substituted with:            -   a C₁ to C₆ alkyl,            -   an alkoxy,            -   a cyano group,            -   a nitro group, or            -   a halogen;    -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a —CH₂O—R_(f) group, where R_(f) is a C₆ to C₈ aryl;    -   a —NR_(g)R_(h) group, where R_(g) is a C₁ to C₆ alkyl or a        hydrogen and R_(h) is a C₆ to C₈ aryl optionally substituted        with an alkoxy;    -   a C₁ to C₆ alkyl;    -   a 5 or 6 membered heteroaryl, optionally substituted with:        -   a C₁ to C₆ alkyl, optionally substituted with a C₆ to C₈            aryl,        -   a C₆ to C₈ aryl, optionally substituted with —COOR_(x),            where R_(x) is as defined above, or        -   an amino group;    -   a 5 or 6 membered heterocycle optionally substituted with:        -   a —COOR_(x) group, where R_(x) is as defined above, or        -   a —NHCOOR_(x) group, where R_(x) is as defined above;    -   a C₆ to C₈ aryl, optionally substituted with one or more of the        following:        -   an alkoxy, optionally substituted with:            -   an alkoxy,            -   a hydroxy,            -   one or more halogens,            -   a 5 or 6 membered heterocycle, optionally substituted                with:                -   a C₁ to C₆ alkyl, or                -   a hydroxy,            -   an amino group optionally substituted with one or more                C₁ to C₆ alkyls,            -   a —NR_(i)SO₂R_(x) group, where R_(x) is as defined above                and R_(i) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —NR_(j)COR_(k) group, where R_(k) is:                -   a C₁ to C₆ alkyl,                -   a hydrogen, or                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,            -   and R_(j) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a haloalkyl, or                -   a haloalkoxy,            -   a —N═N⁺═N⁻ group, or            -   a —COR_(l), where R_(l) is a 5 or 6 membered heterocycle                optionally substituted with a hydroxy,        -   an amino optionally substituted with one or more C₁ to C₆            alkyls,        -   a nitro group,        -   a C₁ to C₆ alkyl group, optionally substituted with:            -   a —NHSO₂R_(x) group, where R_(x) is as defined above, or            -   a —NR_(x)SO₂R_(x) group, where R_(x) is as defined                above,        -   a haloalkoxy,        -   a halogen,        -   a hydroxy,        -   a —COOR_(x) group, where R_(x) is as defined above,        -   a —COR_(m) group, where R_(m) is:            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls, where the C₁ to C₆ alkyls are optionally                substituted with:                -   a hydroxy                -   a 5 or 6 membered heterocycle,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an alkoxy,            -   a 3 to 7 membered heterocycle, optionally substituted                with a C₁ to C₆ alkyl, optionally substituted with a                dialkyl-amino,            -   a —NHR_(n) group, where R_(n) is:                -   a —CH₂CONH₂, or                -   a C₆ to C₈ aryl optionally substituted with:                -    an alkyl,                -    one or more halogens,                -    a nitro group, or                -    one or more alkoxys,        -   a —NR_(o)COR_(p) group, where R_(p) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   an alkoxy, or                -   a C₆ to C₈ aryl,            -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with a halogen,            -   a 5 or 6 membered heteroaryl optionally substituted with                one or more C₁ to C₆ alkyls,            -   a hydrogen,

-   -   -   and where R_(o) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,        -   a —NR_(q)CONR_(q)R_(r) group, where R_(q) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a haloalkyl,            -   a haloalkoxy, or            -   a —COR_(x) group, where R_(x) is as defined above,        -   and where R_(r) is:            -   a C₆ to C₈ aryl optionally substituted with:

-   -   -   -   -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a —OR_(s) group, where R_(s) is a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a C₁ to C₆ alkyl optionally substituted with one or more                of the following:                -   a halogen,                -   an alkylene,                -   a C₆ to C₈ aryl, or                -   a —COOR_(x) group, where R_(x) is as defined above,

            -   a —COOR_(x) group, where R_(x) is as defined above,

        -   a —NR_(t)COOR_(u) group, where R_(u) is:            -   a C₁ to C₁₂ alkyl, optionally substituted with:                -   a C₆ to C₈ aryl optionally substituted with a C₁ to                    C₆ alkyl or an alkoxy,                -   an alkylene,                -   an alkoxy,                -   an alkyne,                -   a halogen, or                -   a 5 or 6 membered heterocycle,            -   a C₆ to C₈ aryl, optionally substituted with:                -   an alkoxy,                -   a halogen, or                -   a C₁ to C₆ alkyl, or            -   a 5 or 6 membered heterocycle,

        -   and R_(t) is:            -   a hydrogen,            -   a C₁ to C₆ alkyl,            -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl, or            -   a haloalkoxy,

        -   a —NR_(v)SO₂R_(w) group, where R_(v) is:            -   a hydrogen,            -   a —COR_(x), where R_(x) is as defined above, or            -   a C₁ to C₆ alkyl, optionally substituted with:                -   a halogen,                -   a —COR_(x) group, where R_(x) is as defined above,                -   a —OCOR_(x) group, where R_(x) is as defined above,                -   a hydroxyl,                -   a hydroxyl, or                -   an alkoxy,

        -   and where R_(w) is:            -   a C₁ to C₆ alkyl optionally substituted with:                -   a halogen,                -   a haloalkyl,                -   a C₆ to C₈ aryl, or                -   a 5 or 6 membered heterocycle,            -   a C₂ to C₆ alkylene,            -   an alkyl- or dialkyl-amino optionally substituted with a                halogen,            -   a 5 or 6 membered heterocycle, or            -   a 5 or 6 membered heteroaryl optionally substituted                with:                -   a C₁ to C₆ alkyl,                -   a 5 or 6 membered heterocycle, or

-   -   -    optionally substituted with a C₁ to C₆ alkyl, where R_(y)            is a C₁ to C₆ alkyl or hydrogen,

-   -   -    where R_(z) is hydrogen or a C₁ to C₆ alkyl, optionally            substituted with a C₆ to C₈ aryl,        -   a —SR_(x) group, where R_(x) is as defined above,        -   a —SO₂R_(aa) group, where R_(aa) is:            -   a C₁ to C₆ alkyl,            -   an amino group,            -   an alkyl- or dialkyl-amino group optionally substituted                with a hydroxy or a —COOR_(x) group, where R_(x) is as                defined above,            -   a 5 or 6 membered heteroaryl,        -   a C₆ to C₈ aryl, or        -   a —NHR_(bb) group, where R_(bb) is:

-   -   -   -   a —C(═S)NH₂ group, or            -   a —PO(OR_(x))₂, where R_(x) is as defined above;

-   -    R_(cc) group, where R_(cc) is:        -   a naphthalene,        -   a 5 or 6 membered heteroaryl,

-   -   -   a C₆ to C₈ aryl, optionally substituted with one or more of            the following:            -   an alkoxy,            -   an hydroxy,            -   a halogen,            -   a C₁ to C₆ alkyl, optionally substituted with a cyano                group,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NHPOR_(x)R_(x), where R_(x) is as defined above,            -   a —NR_(ee)CONR_(ff)R_(ff) group, where R_(ee) is a                hydrogen or a C₁ to C₆ alkyl, optionally substituted                with a halogen, and R_(ff) is:                -   a hydrogen,                -   a haloalkyl,                -   a haloalkoxy,                -   a C₁ to C₆ alkyl, or                -   a —COR_(x), where R_(x) is as defined above,            -   a —NR_(gg)COR_(hh) group, where R_(hh) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl optionally substituted with:                -    an alkoxy,                -    a halogen, or                -    an amino optionally substituted with one or more C₁                    to C₆ alkyls,                -   an amino optionally substituted with one or more C₁                    to C₆ alkyls, where the alkyls are optionally                    substituted with a halogen,                -   a 5 or 6 membered heterocycle,                -   a 5 or 6 membered heteroaryl,            -   and R_(gg) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy, or                -   a —COR_(x) group, where R_(x) is as defined above,            -   a haloalkyl,            -   5 or 6 membered heterocycle groups,            -   an amino optionally substituted with one or more C₁ to                C₆ alkyls,            -   a —NR_(ii)SO₂R_(x) group, where R_(x) is as defined                above, and R_(ii) is:                -   a hydrogen,                -   a C₁ to C₆ alkyl,                -   a haloalkyl,                -   a haloalkoxy,                -   a —COR_(x) group, where R_(x) is as defined above;

-   Z is:    -   a hydrogen;    -   a C₁ to C₆ alkyl optionally substituted with:        -   an alkoxy,        -   one or more halogens, or        -   a C₆ to C₈ aryl;    -   a C₂ to C₆ alkylene;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy or one or        more C₁ to C₆ alkyls;    -   a —COOR_(x) group, where R_(x) is as defined above; or

-   R is a hydrogen, a halogen or an alkoxy;-   R₁ is:    -   a hydrogen;    -   a hydroxy;    -   a halogen;    -   a haloalkyl;    -   a nitro group;    -   a 5 or 6 membered heteroaryl;    -   a 5 or 6 membered heterocycle;    -   an alkoxy optionally substituted with:        -   one or more halogens,        -   a C₆ to C₈ aryl, or        -   a 5 or 6 membered heterocycle;    -   a C₆ to C₈ aryl optionally substituted with an alkoxy;    -   a —COR_(x) group, where R_(x) is as defined above;    -   a C₁ to C₆ alkyl optionally substituted with a dialkyl-amino or        a 5 or 6 membered heterocycle; or-   R₁ joins together with R₂ to form:

-   R₂ is:    -   a nitro group;    -   a hydrogen;    -   a halogen;    -   a hydroxy group;    -   a C₁ to C₆ alkyl group, optionally substituted with one or more        halogens;    -   an amino group;    -   an alkoxy group optionally substituted with:        -   one or more halogens,        -   an —OCOR_(x) group, where R_(x) is as defined above,        -   a dialkyl-amino optionally substituted with an alkoxy,        -   a 5 or 6 membered heterocycle group optionally substituted            with a C₁ to C₆ alkyl,        -   a 5 or 6 membered heteroaryl group, or        -   a C₆ to C₈ aryl group;    -   a —COOR_(x) group, where R_(x) is as defined above;    -   a haloalkyl;    -   an amide group optionally substituted with:        -   a hydroxy group, or        -   a C₆ to C₈ aryl;    -   a 5 or 6 membered heteroaryl;    -   a —OCOR_(x) group, where R_(x) is as defined above;    -   a —NHCOR_(jj) group, where R_(jj) is:        -   an alkoxy, or        -   an amino optionally substituted with one or more C₁ to C₆            alkyls;    -   a —OR_(kk) group, where R_(kk) is a 5 to 6 membered heteroaryl;    -   a —NHSO₂R_(x) group, where R_(x) is as defined above; or-   R₂ joins together with R₁ to form:

-   R₃ is:    -   a hydrogen; or    -   CH₂OCOR_(x), and R_(x) is as defined above;-   or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, a compound or a composition of thepresent invention includes a compound of Formula I, wherein the compoundof Formula I is not

As used herein, the term “alkyl” generally refers to saturatedhydrocarbyl radicals of straight or branched configuration, includingmethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, n-hexyl, n-heptyl, octyl, n-octyl, and the like.In some embodiments, alkyl substituents may be C₁ to C₁₂, or C₁ to C₈ orC₁ to C₆ alkyl groups.

As used herein, “alkylene” generally refers to linear, branched orcyclic alkene radicals having one or more carbon-carbon double bonds,such as C₂ to C₆ alkylene groups including 3-propenyl.

As used herein, “aryl” refers to a carbocyclic aromatic ring structure.Included in the scope of aryl groups are aromatic rings having from fiveto twenty carbon atoms. Aryl ring structures include compounds havingone or more ring structures, such as mono-, bi-, or tricyclic compounds.Examples of aryl groups that include phenyl, tolyl, anthracenyl,fluorenyl, indenyl, azulenyl, phenanthrenyl (i.e., phenanthrene), andnapthyl (i.e., napthalene) ring structures. In certain embodiments, thearyl group may be optionally substituted.

As used herein, “heteroaryl” refers to cyclic aromatic ring structuresin which one or more atoms in the ring, the heteroatom(s), is an elementother than carbon. Heteroatoms are typically O, S or N atoms. Includedwithin the scope of heteroaryl, and independently selectable, are O, N,and S heteroaryl ring structures. The ring structure may includecompounds having one or more ring structures, such as mono-, bi-, ortricyclic compounds. In some embodiments, the heteroaryl groups may beselected from heteroaryl groups that contain two or more heteroatoms,three or more heteroatoms, or four or more heteroatoms. Heteroaryl ringstructures may be selected from those that contain five or more atoms,six or more atoms, or eight or more atoms. Examples of heteroaryl ringstructures include: acridine, benzimidazole, benzoxazole, benzodioxole,benzofuran, 1,3-diazine, 1,2-diazine, 1,2-diazole, 1,4-diazanaphthalene,furan, furazan, imidazole, indole, isoxazole, isoquinoline, isothiazole,oxazole, purine, pyridazine, pyrazole, pyridine, pyrazine, pyrimidine,pyrrole, quinoline, quinoxaline, thiazole, thiophene, 1,3,5-triazine,1,2,4-triazine, 1,2,3-triazine, tetrazole and quinazoline.

As used herein, “heterocycle” refers to cyclic ring structures in whichone or more atoms in the ring, the heteroatom(s), is an element otherthan carbon. Heteroatoms are typically O, S or N atoms. Included withinthe scope of heterocycle, and independently selectable, are O, N, and Sheterocycle ring structures. The ring structure may include compoundshaving one or more ring structures, such as mono-, bi-, or tricycliccompounds. Example of heterocyclo groups include morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl,tetrahydrothiophenyl or tetrahydrothiopyranyl and the like. In certainembodiments, the heterocycle may optionally be substituted.

As used herein, “alkoxy” generally refers to a group with the structure—O—R, where R is an alkyl group as defined above.

For the purposes of this invention, halo substituents may beindependently selected from the halogens such as fluorine, chlorine,bromine, iodine, and astatine. A haloalkyl is an alkyl group, as definedabove, substituted with one or more halogens. A haloalkoxy is an alkoxygroup, as defined above, substituted with one or more halogens.

For the purposes of this invention, where one or more functionalitiesencompassing X, Y, Z, R, R₁, R₂, and R₃, are incorporated into amolecule of Formula (I), each functionality appearing at any locationwithin the disclosed compound may be independently selected, and asappropriate, independently substituted. Further, where a more genericsubstituent is set forth for any position in the molecules of thepresent invention, it is understood that the generic substituent may bereplaced with more specific substituents, and the resulting moleculesare within the scope of the molecules of the present invention.

By “substituted” or “optionally substituted” it is meant that theparticular substituent may be substituted with a chemical group known toone of skill in the art to be appropriate for the referred-tosubstituent, unless a chemical group is specifically mentioned.

Exemplary X substituents include the following, where the * indicatesthe bond of attachment of the scaffold molecule.

Preferred X substituents include —hydrogen; —a cyano group; and —a—COR_(a) group, where R_(a) is: —a C₁ to C₆ alkyl, or —a dialkyl-amino.

Preferred X substituents also include the following, where the *indicates the bond of attachment of the scaffold molecule.

More preferred X substituents include the following, where the *indicates the bond of attachment of the scaffold molecule.

Exemplary Y substituents include the following, where the * indicatesthe bond of attachment of the scaffold molecule.

Preferred Y substituents include the following, where the * indicatesthe bond of attachment of the scaffold molecule.

More preferred Y substituents include the following, where the *indicates the bond of attachment of the scaffold molecule.

Exemplary Z substituents include the following, where the * indicatesthe bond of attachment of the scaffold molecule.

Preferred Z substituents include —a hydrogen; —a C₁ to C₆ alkyloptionally substituted with: —an alkoxy, —one or more halogens, or —a C₆to C₈ aryl; —a C₂ to C₆ alkylene; and —a C₆ to C₈ aryl optionallysubstituted with an alkoxy.

Preferred Z substituents also include the following, where the *indicates the bond of attachment of the scaffold molecule.

More preferred Z substituents include —a hydrogen; —a C₁ to C₆ alkyloptionally substituted with: —a C₆ to C₈ aryl; —a C₂ to C₆ alkylene; and—a C₆ to C₈ aryl optionally substituted with an alkoxy.

More preferred Z substituents include the following, where the *indicates the bond of attachment of the scaffold molecule.

Exemplary R substituents include the following:

Preferred R substituents include the following:

Exemplary R₁ substituents include the following:

Preferred R₁ substituents include —a hydrogen; —a halogen; —a nitrogroup; —a 5 or 6 membered heterocycle; —an alkoxy optionally substitutedwith: —a C₆ to C₈ aryl; —a C₆ to C₈ aryl optionally substituted with analkoxy.

Preferred R₁ substituents also include the following:

More preferred R₁ substituents include the following:

Exemplary R₂ substituents include the following:

Preferred R₂ substituents include —a nitro group; —a hydrogen; —ahalogen; _13 a hydroxy group; —a C₁ to C₆ alkyl group, optionallysubstituted with one or more halogens; an alkoxy group optionallysubstituted with: —one or more halogens, —an —OCOR_(x) group, whereR_(x) is as defined above, —a dialkyl-amino optionally substituted withan alkoxy, —a 5 or 6 membered heterocycle group optionally substitutedwith a C₁ to C₆ alkyl, or —a 5 or 6 membered heteroaryl group; —an amidegroup; and —a —NHSO₂R_(x) group, where R_(x) is as defined above.

Preferred R₂ substituents also include the following:

More preferred R₂ substituents include —a hydrogen; _—a C₁ to C₆ alkylgroup, optionally substituted with one or more halogens; —an alkoxygroup optionally substituted with: —one or more halogens, —a 5 or 6membered heterocycle group optionally substituted with a C₁ to C₆ alkyl,or —a 5 or 6 membered heteroaryl group.

More preferred R₂ substituents also include the following:

Exemplary R₃ substituents include the following:

Preferred R₃ substituents include the following:

Compounds of the invention include the following:

The above compounds were prepared using the schemes and examples setforth below. Other methods of producing these compounds are known to oneof skill in the art.

Preferred compounds include the following compounds in Table A:

TABLE A

More preferred compounds include the following compounds in Table B:

TABLE B

B. Preparation of Compounds of the Invention

Indole compounds of the present invention can be obtained via standard,well-known synthetic methodology. Many of the indole starting materialscan be prepared the routes described below or by those skilled in theart.

Compounds of formula I, represented by structure II can be prepared bythe methodology depicted in Scheme A below:

An α-nitroketone derivative A2 can be derived from treatment of theanion of nitromethane, obtained from the treatment of nitromethane witha base, such as, e.g., sodium or potassium t-butoxide or sodium hydride,with an activated carboxylic acid derivative, e.g., the acyl imidazolideA1. Reaction of the α-nitroketone A2 with amine derivative A3 can affordthe nitro enamine A4 by mixing the components A3 and A4 and heating in asuitable solvent such as an alcohol or an aprotic solvent. Treatment ofthe nitro enamine A4 with quinone A5 in a polar protic solvent such asacetic acid at or near ambient temerature gives the compound of formulaII.

Compounds of formula I, represented by structure III can be prepared asshown in Scheme B below:

Treatment of B1 with a reactive alkyl or aryl group containing a leavinggroup L in a suitable solvent, with or without heat in the presence of abase, such an inorganic base, e.g., sodium or potassium carbonate or anorganic base, e.g., triethylamine, can afford the compound of structureIII. Examples of leaving groups include but are not limited to halogens(e.g., chlorine, bromine or iodine) or alkyl or arylsulfonates.

Compounds of formula I, represented by structure IV can be prepared asshown in Scheme C below:

Compounds of structure IV can be obtained by nitrating an indole ofstructure C1, to give the 3-nitroindole C2. The nitration can be carriedout by treatment of C1 with a nitrating agent, such as nitric acid orsodium nitrite in a solvent such as acetic acid, acetic anhydride,sulfuric acid or in a mixed solvent system containing an organic solventsuch as dichloromethane. The reaction can be carried out a temperatureof −30° C. to +50° C. Treatment of C2 with a reactive functional groupR₉ containing a suitable leaving group L (C3) can give compounds ofstructure IV. Reactive functional groups can consist of but are notlimited to alkyl and aralkyl. L can represent a halide, particularlychloro, bromo or iodo or an alkylsulfonate. The reaction between C2 andC3 can be carried out in a suitable solvent in the presence of aninorganic base such as potassium carbonate or sodium hydride or anorganic base such as a trialkylamine. Alternatively, the group R₉ canrepresent an aryl or heteroaryl group and L can represent a halide,particularly chloro, bromo or iodo. The reaction can be carried out in apolar or nonpolar solvent at a temperature from ambient to 200° C. inthe presence of a copper catalyst, e.g., CuI, a base such as Cs₂CO₃ orK₃PO₄, and optionally an amine ligand such as 1,2-bis(methylamino)ethaneor 1,2-cyclohexanediamine.

An alternative pathway is to convert C1 into C4 in similar fashion asdescribed above and then carry out the nitration reaction to affordcompounds of structure IV.

Compounds of formula I, represented by structure V can be prepared asshown in Scheme D.

Treatment of β-ketoesters of structure D1 with amines D2 gives the aminocrotonate derivatives D3 by heating in a suitable solvent such as analcohol or an aprotic solvent. Reaction between D3 and quinone D4 in apolar protic solvent, such as acetic acid gives compounds of structureV.

Compounds of the present invention, represented by structure VIcompounds can be prepared by the chemistry described in scheme E below.

Indole-3-carboxylic esters E1 can be converted to indole-3-carboxylicacids E2 by treatment of compounds of structure E1 with, for example,either acid or base in aqueous or mixed aqueous-organic solvents atambient or elevated temperature or by treatment with nucleophilicagents, for example, boron tribromide or trimethylsilyl iodide, in asuitable solvent. Compounds of type E2 can then be activated and treatedwith amines of type E3 to give compounds E4. Activation of thecarboxylic acid can be carried out, for example, by any of the standardmethods. For example, the acid E2 can be activated with couplingreagents such as EDCI or DCC with or without HOBt in the presence of theamine E3, or alternatively the acid can be activated as the acidchloride by treatment of the acid with, e.g., thionyl chloride or oxalylchloride or as the acyl imidazolide, obtained by treatment of the acidwith carbonyl diimidazole, followed by treatment of the amine E3.Compounds E4 can be converted to compounds of structure VI by treatmentof E4 with a reactive functional group R₉ containing a suitable leavinggroup L (E5) as described previously. Alternatively, compounds of typeE1 can be converted to compounds of structure E6 by treatment with E5.Indole-3-carboxylic esters E6 can then be converted toindole-3-carboxylic acids E7 by the methods described above. Conversionof E7 to compounds of structure VI can be carried out by the activationand reaction with an amine E3 as described above.

Compounds of the present invention, represented by structure VIIcompounds can be prepared by the chemistry described in scheme F below.

Indoles F1 can be formylated with reagents such as phosphorousoxychloride in the presence of DMF to give the indole-3-carboxaldehydesF2. Conversion to compounds of structure VII can be accomplished bytreatment of F2 with compounds F3 as described previously.Alternatively, compounds of type F1 can first be converted to F4 andthen be formylated to compounds of structure VII.

Compounds of formula G, represented by structure VIII can be prepared asshown in Scheme G.

Indole-3-carboxaldehydes of structure G1 can be converted to theindole-3-carboxylic acid derivatives by oxidation with reagents such aspotassium permanganate under aqueous conditions.

Compounds of formula H, represented by structure IX can be prepared asshown in Scheme H.

Indole-3-carboxaldehydes of structure H1 can be converted to theindole-3-carbonitrile derivatives H2 by a variety of methods. Treatmentof H1 with a nitroalkane, e.g., nitropropane, in the presence of anamine source, e.g., ammonium hydrogen phosphate gives theindole-3-carbonitrile H2 derivative. An alternative pathway to compoundH2 is via the intermediate H3. Conversion of H1 to the oxime derivativeH3 can be followed by dehydration, e.g., treatment of the oxime withacetic anhydride and a base, or reaction of the oxime with thionylchloride to give H2. The compound H2 can then be reacted with a reactivefunctional group R₉ containing a suitable leaving group L (H4) asdescribed previously to afford compounds of structure IX.

Alternatively, H1 can be reacted with a reactive functional group R₉containing a suitable leaving group L (H4) to give the intermediate H5which can be reacted with a nitroalkane as above to give theindole-3-carbonitrile IX compound. Compound IX can also be obtained byconversion to the oxime H6 followed by a dehydration reaction asdescribed above.

Compounds of the present invention, represented by structure X can alsobe prepared as described in scheme I below.

Indoles I1 can be cyanated with an appropriate cyanating agent, e.g.,chlorosulfonyl isocyanate (I2) or a dialkyl phosphoryl isocyanate in asuitable solvent or solvent mixture, e.g. DMF, CH₃CN or dioxane, toafford compounds of structure I3. The compound I3 can then be reactedwith a reactive functional group R₉ containing a suitable leaving groupL (I4) as described previously afford the compound X.

Alternatively, compound I1 can be reacted with a reactive functionalgroup R₉ containing a suitable leaving group L to give compounds ofstructure 15 which can then be cyanated as above to give compounds offormula X.

Compounds of formula J, represented by structure XI can be prepared asshown in Scheme J.

Amino crotonates J1 can be reacted with amines J2 to give J3. Reactionof J3 with quinone in the presence of a polar, protic solvent, e.g.,acetic acid, gives the compound of structure XI.

Compounds of the present invention, represented by structure XII andXIII can be prepared as described in scheme K below.

Aldehydes of structure K1 can be reacted with an alkyl azidoacetate K2by heating the components together in a suitable organic solvent, e.g.,a protic or non-protic solvent, in the presence of an organic orinorganic base, to give the α-azidoacrylate K3. Heating K3 in thepresence of a suitable non-reactive organic solvent, e.g., toluene orxylenes can give the 2-alkoxycarbonylindoles K4. Reduction of the esterfunctionality with a suitable reducing reagent, for example, lithiumaluminum hydride, in a suitable solvent, e.g., ether or THF can give theintermediate K5. Reaction of K5 with a reactive functional group R₉containing a suitable leaving group L (K6) as described in previouslyaffords the compound K7. Cyanation of K7 with a cyanating agent, e.g.,chlorosulfonyl isocyanate as described previously can give compound XII.Alternatively, cyanation of K5 with chlorosulfonyl isocyanate gives K8,which can be reacted with a reactive functional group R₉ containing asuitable leaving group L (K6) as described previously, affords, thecompound XII.

An alternative use of intermediate K4 is exemplified below. Hydrolysisof the 2-alkoxycarbonyl group of the indole K4 either under acidic orbasic conditions followed by decarboxylation can give the intermediateK9. Decarboxylation can be carried out thermally, i.e., heating in anappropriate solvent, e.g., toluene, xylenes, or quinoline.Alternatively, a source of copper can be added, for example, copperbronze, to facilitate decarboxylation. Reaction of K9 with a reactivefunctional group R₉ containing a suitable leaving group L (K6) asdescribed above can afford the compounds K10. Cyanation of K10 with acyanating agent, e.g., chlorosulfonyl isocyanate as described previouslycan give compound XIII. Alternatively, cyanation of K9 withchlorosulfonyl isocyanate gives K11, which can be reacted with areactive functional group R₉ containing a suitable leaving group L (K6)as described in previously, affords the compound XIII.

Compounds of formula L, represented by structure XIV can be prepared asshown in Scheme L.

Compounds of formula L1 can be halogenated on the 2-methyl group to give2-bromomethyl or chloromethyl indoles L2. The halogenation reaction canbe conducted with reagents, e.g., N-bromo- or chlorosuccinimide. Thereaction can be conducted in a suitable solvent, such as chloroform,carbon tetrachloride, or THF and carried out in a range between ambienttemperature and 80° C. Optionally, a radical initiator may be added,e.g., benzoyl peroxide or AIBN. The compound L2 can then be reacted witha nucleophile R₅—W (L3) to give compounds of structure XIV. The reactioncan be conducted in a suitable solvent, e.g., THF, CH₂Cl₂ or DMF, withina temperature range of 0° C. to 120° C. A base, e.g., an inorganic base,such as potassium carbonate or an organic base, such as a trialkylaminecan be used to remove the acid formed in the reaction. The group W canrefer to an N, O or S atom.

Compounds of the present invention, represented by structure XV can beprepared as described in scheme M below.

Anilines of structure M1 can be diazotized and the resulting diazoniumsalt can be reduced to give the phenyl hydrazine compound M2. Reactionbetween the hydrazine M2 and a ketone M3 under acidic conditions cangive the indole compound M4. The conditions for the cyclization reactioncan be carried out under typical conditions utilized by one skilled inthe art, for example, acidic conditions, utilizing acids such as aBronstead acid ,e.g., acetic acid, hydrochloric acid or polyphosphoricacid or a Lewis acid, e.g., zinc chloride. The reaction can be carriedout in the presence of a co-solvent, e.g., CH₂Cl₂ or THF typicallywithin a temperature range of 0° C. to 120° C. Reaction of M4 with areactive functional group R₉ containing a suitable leaving group L (M5)as described previously, can afford compounds M6. Cyanation of theindole M6 with a cyanating agent such as chlorosulfonyl isocyanate cangive the compound of structure XV.

Alternatively, the indole M4 can be cyanated to give compounds ofstructure M7. Reaction of M7 with a reactive functional group R₉containing a suitable leaving group L (M5) as described above can givecompounds of structure XV.

Compounds of formula I, represented by structure XVI can be prepared asshown in Scheme N.

Compounds of formula N1 can be reacted with a dialkylformamide dialkylacetal, N2, e.g., dimethylformamide dimethyl acetal, optionally in thepresence of a suitable solvent, e.g., DMF or dioxane, at a temperaturerange from ambient to 150° C. to give the compound of structure N3.Reduction of the nitro group of compounds of type N3 under standardconditions can give the indole compounds of structure N4. The reductioncan be carried out via hydrogenation, using a sub-stoichiometric amountof a hydrogenation catalyst, e.g., platinum or palladium, in thepresence of a hydrogen source in a protic or aprotic solvent. Thereduction can be carried out in a temperature range of ambient to 80° C.Alternatively, the reduction can be carried out via chemical reduction,e.g., in the presence of stoichiometric amounts of Fe or Sn compounds ina suitable solvent at a temperature range of ambient to 100° C. Thecompound N4 can then be reacted with a reactive functional group R₉containing a suitable leaving group L (N5) as described previously toafford compounds of structure N6. Cyanation of N6 with a cyanating agentsuch as chlorosulfonyl isocyanate in a suitable solvent can give thecompounds of structure XVI.

Alternatively, compounds of structure N4 can be cyanated to givecompounds of structure N7. Reaction with N7 with a reactive functionalgroup R₉ containing a suitable leaving group L (N5) as described abovecan give compounds of structure XVI.

Compounds of formula I, represented by structure XVII can be prepared asshown in Scheme O.

Compounds of structure O1 can be converted to 2-iodo- or bromoindolesO2. Typically, a strong base, such as n-butyllithium or s-butyllithiumor lithium diisopropylamide or lithium or potassium hexamethyldisilazideis employed, with formation of the 2-indolyl anion generated in asuitable unreactive solvent, e.g., ether or THF, or solvent mixturescontaining them. The reaction is typically carried out in the range of−78° C. to ambient temperature. The 2-indolyl anion can then be quenchedwith an electrophilic source of halogen, including but not limited toiodine, bromine or N-bromosuccinimide to give compounds of structure O2.Reaction of 2-iodo- or bromoindoles O2 with a boronic acid (commonlyreferred to as a Suzuki reaction) or trialkyl stannane (commonlyreferred to as a Stille reaction) can give the compounds of structureXVII. The coupling reactions are carried out by methods known to thoseskilled in the art and include conducting the reaction in the presenceof a catalyst, such as tetrakis (triphenylphosphine) palladium (0), bis(triphenylphosphine) palladium (II) dichloride or palladium acetate withadded phosphine ligand. The reactions are carried out in a suitablesolvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at atemperature range of ambient to 150° C. For the Suzuki reaction, a baseis usually added. The base can be in aqueous solution, e.g., aqueoussodium carbonate or sodium bicarbonate, or the base can be employedunder anhydrous conditions, e.g., cesium or potassium fluoride. For theStille reaction a copper co-catalyst, e.g., copper iodide, can be added.

Alternatively, indoles O1 can be converted to the indole-2-boronic acidor indole-2-trialkylstannane derivatives O3 by reacting the 2-indolylanion described above with a trialkylborate or chlorotrialkyl stannanederivative, respectively. Compounds of type O3 can be reacted with aryland heteroaryl bromides and iodides under similar conditions to thosedescribed above to form compounds of structure XVII.

Compounds of formula I, represented by structure XVIII can be preparedas shown in Scheme P.

Compounds of structure P1 can be converted to compounds P3 by treatmentof P1 with an aryl or heteroaryl halide (P2) in the presence oforganometallic catalysis. Such catalyst combinations can includepalladium catalysts, e.g., palladium acetate and a source of copper,e.g., copper iodide. The reaction can be carried out in the presence ofa base, e.g., cesium carbonate. The reaction can be carried out within atemperature range of ambient temperature to 150° C.

Compounds of the present invention, represented by structure XIX can beprepared as described in scheme Q below.

Compounds of structure XIX can be prepared by protecting an indolecompound of structure Q1 as e.g., the N-Boc derivative Q2.Alternatively, other protecting groups which can be utilized but notlimited to include , e.g., benzyl, alkyl or aryl sulfonyl, or trialkylsilyl. Treatment of Q2 with a strong base, e.g., lithium diisopropylamide in an aprotic solvent, e.g., THF followed by quenching with atrialkylborate derivative can give the indolyl-2-boronic acid Q3.Reaction with an aryl or heteroaryl halide Q4 in the presence ofpalladium catalysis, e.g., tetrakis (triphenylphosphine) palladium (0),bis (triphenylphosphine) palladium (II) dichloride or palladium acetatewith added phosphine ligand, can give the compound Q5. Removal of theprotecting group can give Q6. Reaction with Q6 with a reactivefunctional group R₉ containing a suitable leaving group L as describedabove can give compounds of structure Q7. Cyanation of compound Q7 cangive the compounds of structure XIX.

Compounds of formula I, represented by structure XX can be prepared asshown in Scheme R.

Compounds of structure R1 can be prepared by protecting an indolecompound of structure R1 as e.g., the N-Boc derivative R2 as above.Compounds of structure R2 can be converted to 2-iodo- or bromoindolesR3. Typically, a strong base, such as n-butyllithium or s-butyllithiumor lithium diisopropylamide or lithium or potassium hexamethyldisilazideis employed, with formation of the 2-indolyl anion generated in asuitable unreactive solvent, e.g., ether or THF, or solvent mixturescontaining them. The reaction is typically carried out in the range of−78° C. to ambient temperature. The 2-indolyl anion can then be quenchedwith an electrophilic source of halogen, including but not limited toiodine, bromine or N-bromosuccinimide to give compounds of structure R3.After removal of the protecting group, compounds of R4 can be reactedwith aryl or heteroaryl boronic acids or esters (R5) (commonly referredto as a Suzuki reaction) to give compounds of structure R6. The couplingreactions are carried out by methods known to those skilled in the artand include conducting the reaction in the presence of a catalyst, suchas tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine)palladium (II) dichloride or palladium acetate with added phosphineligand. Reaction with R6 with a reactive functional group R₉ containinga suitable leaving group L as described above can give compounds ofstructure XX.

Compounds of the present invention, represented by structure XXI can beprepared as described in scheme S below.

2-iodo- or bromoindoles of structure S1 can be reacted with alkenes inthe presence of a palladium catalyst (commonly referred to as the Heckreaction) to give compounds of type XXI. The coupling reactions can becarried out by methods known to those skilled in the art. The choice ofcatalyst and solvents are similar to those described previously.

Compounds of formula I, represented by structure XXII can be prepared asshown in Scheme T.

2-Iodo- or 2-bromoindoles of structure T1 can be reacted with acetylenesin the presence of a palladium catalyst (commonly referred to as theSonagashira reaction) to give compounds of type XXII. The couplingreactions can be carried out by methods known to those skilled in theart. A typical set of reaction conditions includes reacting the indolesof structure T1 with an acetylene compound T2 in the presence of asource of palladium, a copper co-catalyst and an amine source. Thereaction is carried out in a suitably unreactive solvent and conductedwithin a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXIII can be preparedas shown in Scheme U.

Compounds of structure XXIII can be obtained from the reduction ofcompounds XXI and XXII. Conditions for the reduction can include, butare not limited to catalytic reduction, e.g., hydrogenation over asource of platinum or palladium in a suitable solvent, e.g., CH₂Cl₂,ether, THF, methanol or solvent combinations.

Compounds of the present invention, represented by structure XXIV can beprepared as described in scheme V below.

Indoles of structure VI can be reacted with a suitable base, such aslithium diisopropylamide or potassium hexamethyldisilazide to generatethe 2-indolyl anion in a suitable unreactive solvent, e.g., ether orTHF, or solvent mixtures containing them. The reaction is typicallycarried out in the range of −78° C. to ambient temperature. The2-indolyl anion can then be quenched with a source of zinc halide, e.g.,zinc halide metal or soluitions containing them to give organozinccompounds of structure V2. Reaction of V2 with an arylhalide (V3) in thepresence of a palladium catalyst (commonly referred to as the Negishireaction) gives compounds of structure XXIV. Alternatively, 2-iodo orbromoindoles of structure V4, prepared from compounds V1 as describedpreviously, can be reacted with organozinc compounds of structure V5 inthe presence of a suitable palladium catalyst to give compounds ofstructure XXIV. The organozinc compound V5 can be derived from, e.g., analkyl or alkenyl halide after treatment with activated zinc or an arylor heteroaryl lithium or magnesium comound after treatment with zinchalide. Furthermore, the reactions of V2 or V4 can be carried out in thepresence of a palladium source, e.g., as tetrakis (triphenylphosphine)palladium (0) or bis (triphenylphosphine) palladium (II) dichloride in asuitable solvent and at a temperature range from ambient to 150° C.

Compounds of formula I, represented by structure XXV-XXVIII can beprepared as shown in Scheme W.

2-Iodo- or bromoindoles of structure W1 can be reacted with acetylenesof structure W2 in the presence of a palladium catalyst (commonlyreferred to as the Sonagashira reaction) to give compounds of type XXV.The coupling reactions can be carried out by methods known to thoseskilled in the art. A typical set of reaction conditions includesreacting the indoles of structure W1 with an acetylene compound W2 inthe presence of a source of palladium, an optional copper co-catalystand an amine source. The reaction is carried out in a suitablyunreactive solvent and conducted within a temperature range from ambientto 150° C. Reaction with XXV with a reactive functional group R₉containing a suitable leaving group L as described above can givecompounds of structure XXVI.

2-iodo- or bromoindoles of structure W1 can also be reacted with alkenesin the presence of a palladium catalyst (commonly referred to as theHeck reaction) to give compounds of type XXVII. The coupling reactionscan be carried out by methods known to those skilled in the art. Thechoice of catalyst and solvents are similar to those describedpreviously. Reaction with XXVII with a reactive functional group R₉containing a suitable leaving group L as described above can givecompounds of structure XXVIII.

Compounds of formula I, represented by structure XXIX can be prepared asshown in Scheme X.

Indoles of structure X1 and be acylated with acyl halides of structureX2 to give compounds of structure XXIX. The reaction can be promotedwith a Lewis acid. The choice of Lewis acid can be chosen from, but isnot limited to aluminum chloride, ferric chloride, stannic chloride ordiethyl aluminum. The reaction is typically carried out in a suitablenon-reactive solvent including CH₂Cl₂, carbon disulfide ordichloroethane and is typically conducted within a temperature range of−20° C. to 80° C.

Compounds of formula I, represented by structure XXX can be prepared asshown in Scheme Y.

3-Cyanoindoles of structure Y1 can be converted to tetrazoles ofstructure Y2 by treatment with, e.g., sodium azide. Heating a mixture ofY2 and the reagent Y3 can give the 3-(1,2,4-oxadiazolyl)indole compoundXXX. The reagent Y3 can be, e.g., an acyl halide or an acid derivativeactivated with a reagent such as dicyclohexyl carbodiimide ordiisopropyl carbodiimide. The reaction can be carried out in a varietyof solvents, including e.g., toluene, dioxane, pyridine anddichloroethane and can be carried out by heating Y2 and Y3 at atemperature range of 30° to 130° C.

Compounds of formula I, represented by structure XXXI can be prepared asshown in Scheme Z.

3-Cyanoindoles of structure Z1 can be treated with hydroxylamine to givehydroxyamidine compounds of formula Z2. Reaction of hydroxyamidines ofstructure Z2 with compounds of structure Z3 can giveO-acylhydroxyamidines Z4. Compounds Z3 can represent, for example, acylhalides or carboxylic acids activated with a reagent such asdicyclohexyl carbodiimide or diisopropyl carbodiimide. Heating compoundsof structure Z4 in a non-reactive organic solvent, e.g., toluene,dichloroethane or dioxane in a temperature range of 30° C. to 150° C.can give compounds of structure XXXI.

Compounds of the present invention, represented by structure XXXII canbe prepared as described in scheme AA below.

Ketoindoles of type AA1 can be converted to oximes of structure AA2 byheating the ketoindoles with hydroxylamine (free base or acid salt) in asuitable solvent. Bis-deprotonation of compounds of type AA2 with astrong organic base (e.g., n-butyllityium or sec-butyllithium ortert-butyllithium) followed by reaction with DMF can give compounds offormula XXXII.

Compounds of formula I, represented by structure XXXIII can be preparedas shown in Scheme AB.

3-Ketoindoles of structure AB1 can be homologated to vinylogous amidesof structure AB3 by reaction with dialkyl amide dialkyl acetals AB2. Thedialkyl amides can include e.g., lower alkyl amides such as formamide,acetamide and propionamide. Examples would include dimethlformamidedimethyl acetal and dimethyl acetamide dimethyl acetal. The reaction canbe conducted by reacting AB1 and AB2 with or without additional solventat a temperature from ambient to 150° C. Treatment of AB3 withhydroxylamine (free base or acid salt) in a suitable solvent can givecompounds of structure XXXIII. The reaction is typically conductedwithin a temperature range from ambient to 120° C.

Compounds of formula I, represented by structure XXXIV can be preparedas shown in Scheme AC.

Vinylogous amides of structure AC1 (as prepared above) can be treatedwith hydrazines AC2 in a suitable organic solvent (DMF, alcohol oracetic acid) at temperatures ranging from ambient temperature to 150° C.to give compounds of structure XXXIV.

Compounds of the present invention, represented by structure XXXV can beprepared as described in scheme AD below.

Indole-3-carboxaldehydes of structure AD1 (as prepared in Scheme F) canbe reacted with p-(toluenesulfonyl)methyl isocyanate (TOSMIC) in thepresence of a base to give compounds of structure XXXV. Bases caninclude potassium carbonate or 1,8-diazabicyclo[5.4.0]undec-7-ene andthe reaction can be carried out in a suitable organic solvent fromambient temperature to 150° C.

Compounds of formula I, represented by structure XXXVI and XXXVII can beprepared as shown in Scheme AE.

3-Indolecarboxylic acids of structure AE1 (from Scheme E) can beconverted to amides of structure AE2. Compounds of structure AE2 can beactivated by any of the standard methods. For example, the acid AE1 canbe activated with coupling reagents such as EDCI or DCC with or withoutHOBt in the presence of ammonia. Alternatively, the acid can beactivated as the acid chloride or as the acyl imidazolide as describedpreviously, followed by treatment of ammonia.

The indole-3-carboxamides of structure AE2 can be reacted withsubstituted aldehydes or ketones (AE3) containing a suitable leavinggroup L, in a suitable solvent at temperatures above ambient and up to200° C. The reaction can be performed with or without added base toafford oxazoles of structure XXXVI.

The indole-3-carboxamides of structure AE2 can also be converted tothioamides of structure AE4 by treating the primary amides withLawesson's reagent or phosphorous pentasulfide at or above ambienttemperature in a suitable organic solvent. The resulting thioamides AE4can be reacted with substituted aldehydes or ketones containing asuitable leaving group L (AE3), in a suitable solvent at temperaturesabove ambient and up to 150° C. The reaction can be performed with orwithout added base to afford thiazoles of structure XXXVII.

Compounds of the present invention, represented by structure XXXVIII andXXXIX can be prepared as described in scheme AF below.

3-Ketoindoles of structure AF1 can be halogenated (e.g., brominated) togive compounds of structure AF3. Suitable brominating agents can includebut are not limited to phenyltrimethylammonium tribromide (AF2),N-bromosuccinimide or bromine and can be carried out in a variety oforganic solvents.

Treatment of compounds AF3 with amides of type AF4 in a suitable solventat temperatures above ambient and up to 200° C. with or without addedbase can give oxazoles of structure XXXVIII.

Treatment of compounds AF3 with thioamides of type AF5 in a suitablesolvent at temperatures above ambient and up to 150° C. with or withoutadded base can give thiazoles of structure XXXIX.

Compounds of formula I, represented by structure XL can be prepared asshown in Scheme AG.

Indoles of structure AG1 can be brominated or iodinated to givecompounds of structure AG2. Brominating agents may include but arenotlimited to bromine or N-bromosuccinimide and iodinating reagents mayinclude iodine monochloride or bis-trifluoroacetoxy iodobenzene.Reaction of 3-iodo- or bromoindoles AG2 with a boronic acid AG3(commonly referred to as a Suzuki reaction) can give the compounds ofstructure XL. The coupling reactions are carried out by methods known tothose skilled in the art and include conducting the reaction in thepresence of a catalyst, such as tetrakis (triphenylphosphine) palladium(0), bis (triphenylphosphine) palladium (II) dichloride or palladiumacetate with added phosphine ligand. The reactions are carried out in asuitable solvent, e.g., DMF, toluene, dimethoxy ethane or dioxane at atemperature range of ambient to 150° C. and typically in the presence ofa base e.g., aqueous sodium carbonate or sodium bicarbonate, or the basecan be employed under anhydrous conditions, e.g., cesium or potassiumfluoride.

Alternatively, indole AG2 can be converted to the indole-3-boronic acidderivative AG5 by reacting the 3-haloindole AG2 with a strong organicbase (alkyllithium or grignard reagent) and reacting the resultant anionwith a trialkylborate reagent AG4. Compounds of type AG5 can be reactedwith aryl and heteroaryl bromides and iodides under similar conditionsto those described above to form compounds of structure XL.

Compounds of the present invention, represented by structure XLI can beprepared as described in scheme AH below.

3-iodo- or bromoindoles of structure AH1 can be reacted with alkenes AH2in the presence of a palladium catalyst (commonly referred to as theHeck reaction) to give compounds of type XLI. The coupling reactions canbe carried out by methods known to those skilled in the art. The choiceof catalyst and solvents are similar to those described in Scheme AG.

Compounds of formula I, represented by structure XLII can be prepared asshown in Scheme AI.

3-Iodo- or bromoindoles of structure AI1 can be reacted with acetylenesAI2 in the presence of a palladium catalyst (commonly referred to as theSonagashira reaction) to give compounds of type XLII. The couplingreactions can be carried out by methods known to those skilled in theart. A typical set of reaction conditions includes reacting the indoleof structure AI1 with an acetylene compound AI2 in the presence of asource of palladium, a copper co-catalyst and an amine source andcarrying out the reaction at a temperature range of ambient to 150° C.

Compounds of the present invention, represented by structure XLIII andXLIV can be prepared as described in scheme AJ below.

Nitroanilines of structure AJ1 can be converted to indoles of structureXLIII by condensation and cyclization with nitriles of structure AJ2.The reaction can be carried out in a suitable organic solvent, e.g., DMFor dioxane. Treatment of compounds of structure XLIII with a basefollowed by reaction with a reactive functional group R₉ containing asuitable leaving group L can give the compounds of formula XLIV.

Compounds of formula I, represented by structure XLV-XLVIII can beprepared as shown in Scheme AK.

2-aminoindoles of structure XLV can be alkylated with a reactivefunctional group R₁₅ containing a suitable leaving group L in thepresence of a base, e.g., sodium hydride or potassium carbonate in asuitable organic solvent to give compounds of structure XLVI. A secondalkylation utilizing a reactive functional group R′₁₅ containing asuitable leaving group L similarly can give compounds of structureXLVII.

Acylation of compounds of structure XLV with acyl chlorides of structureAK1 can give compounds of structure XLVIII. The reaction is typicallycarried out in the presence of an organic base, e.g., a trialkylamine oran inorganic base, e.g., potassium carbonate in a suitable organicsolvent.

Compounds of the present invention, represented by structure XLIX can beprepared as described in scheme AL below.

Indole-3-carboxylic acids of structure AL1 can be activated to givecompounds of structure AL2. Compounds of structure AL2 can represent,for example, acyl halides or carboxylic acids activated with a reagentsuch as dicyclohexyl carbodiimide or diisopropyl carbodiimide. Reactionof compounds of structure AL2 with hydroxyamidines of structure AL3 cangive O-acylhydroxyamidines AL4. Hydroxyamidines may be obtainedcommercially or by treatment of nitrile compounds with hydroxylamine.Heating compounds of structure AL4 in a non-reactive organic solvent,e.g., toluene, dichloroethane or dioxane in a temperature range of 30°C. to 150° C. can give compounds of structure XLIX.

C. Methods of the Invention

The methods of the invention generally comprise administering atherapeutically effective amount of one or more compound of the presentinvention to a subject in need of treatment for HCV infection. In apreferred embodiment, a therapeutically effective amount of acomposition comprising a compound of Formula I as described herein isadministered to a subject in need of treatment. In another preferredembodiment, in another preferred embodiment, a compound or a compositionused in the methods of the present invention includes a compound ofFormula I as described herein wherein the compound of Formula I is not

Compound 1.

The compound(s) of the present invention may be administered to thesubject via any drug delivery route known in the art. Specific exemplaryadministration routes include oral, ocular, rectal, buccal, topical,nasal, ophthalmic, subcutaneous, intramuscular, intraveneous (bolus andinfusion), intracerebral, transdermal, and pulmonary. Individualsinfected with HCV can be treated with the compounds of the presentinvention to prevent or reduce further replication of HCV.

The term therapeutically effective amount, as used herein, refers to anamount of a compound of the present invention effective to inhibit HCVtranslation, thereby effectively treating or ameliorating the HCVinfection. The effect of the compound can be determined by analyzing (1)the presence of HCV-RNA; (2) the presence of anti-HCV antibodies; (3)the level of serum alanine amino transferase (ALT) and aspartateaminotransferase (AST) (ALT and AST are elevated in patients chronicallyinfected with HCV); and (4) hepatocellular damage. The precise effectiveamount for a subject will depend upon the subject's body weight, sizeand health. Therapeutically effective amounts for a given patient can bedetermined by routine experimentation that is within the skill andjudgment of the clinician.

For any compound, the therapeutically effective amount can be estimatedinitially either in cell culture assays or in relevant animal models,such as marmosets and tarmarins. The animal model may also be used todetermine the appropriate concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in humans. Therapeutic efficacy andtoxicity may be determined by standard pharmaceutical procedures in cellcultures or experimental animals, e.g., ED₅₀ (the dose therapeuticallyeffective in 50% of the population) and LD₅₀ (the dose lethal to 50% ofthe population). The dose ratio between therapeutic and toxic effects isthe therapeutic index, and it can be expressed as the ratio, ED₅₀/LD₅₀.Pharmaceutical compositions that exhibit large therapeutic indices arepreferred. The dosage contained in such compositions is preferablywithin a range of circulating concentrations that include an ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed, sensitivity of the patient, and the routeof administration.

More specifically, the concentration-biological effect relationshipsobserved with regard to the compound(s) of the present inventionindicate an initial target plasma concentration ranging fromapproximately 0.1 μg/ml to approximately 100 μg/mL, preferably fromapproximately 1 μg/mL to approximately 50 μg/mL, more preferably fromapproximately 5 μg/mL to approximately 50 μg/mL, even more preferablyfrom approximately 10 μg/mL to approximately 25 μg/mL. To achieve suchplasma concentrations, the compounds of the invention may beadministered at doses that vary from 0.1 μg to 100,000 mg, dependingupon the route of administration. Guidance as to particular dosages andmethods of delivery is provided in the literature and is generallyavailable to practitioners in the art. In general the dose will be inthe range of about 1 mg/day to about 10 g/day, or about 0.1 g to about 3g/day, or about 0.3 g to about 3 g/day, or about 0.5 g to about 2 g/day,in single, divided, or continuous doses for a patient weighing betweenabout 40 to about 100 kg (which dose may be adjusted for patients aboveor below this weight range, particularly children under 40 kg).

The exact dosage will be determined by the practitioner, in light offactors related to the subject that requires treatment. Dosage andadministration are adjusted to provide sufficient levels of the activeagent(s) or to maintain the desired effect. Factors which may be takeninto account include the severity of the disease state, general healthof the subject, age, weight, and gender of the subject, diet, time andfrequency of administration, drug combination(s), reactionsensitivities, and tolerance/response to therapy. Long-actingpharmaceutical compositions may be administered every 3 to 4 days, everyweek, or once every two weeks depending on half-life and clearance rateof the particular formulation.

D. Metabolites of the Compounds of the Invention

Also falling within the scope of the present invention are the in vivometabolic products of the compounds described herein. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammalian tissue or a mammal for a period of time sufficient toyield a metabolic product thereof. Such products typically areidentified by preparing a radio-labeled (e.g. C¹⁴ or H³) compound of theinvention, administering it in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to a mammal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours), and isolating its conversion productsfrom urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS or NMR analysis. In general, analysis of metabolites may be done inthe same way as conventional drug metabolism studies well-known to thoseskilled in the art. The conversion products, so long as they are nototherwise found in vivo, are useful in diagnostic assays for therapeuticdosing of the compounds of the invention even if they possess nobiological activity of their own.

E. Pharmaceutical Compositions of the Invention

While it is possible for the compounds of the present invention to beadministered neat, it may be preferable to formulate the compounds aspharmaceutical compositions. As such, in yet another aspect of theinvention, pharmaceutical compositions useful in the methods of theinvention are provided. The pharmaceutical compositions of the inventionmay be formulated with pharmaceutically acceptable excipients such ascarriers, solvents, stabilizers, adjuvants, diluents, etc., dependingupon the particular mode of administration and dosage form. Thepharmaceutical compositions should generally be formulated to achieve aphysiologically compatible pH, and may range from a pH of about 3 to apH of about 11, preferably about pH 3 to about pH 7, depending on theformulation and route of administration. In alternative embodiments, itmay be preferred that the pH is adjusted to a range from about pH 5.0 toabout pH 8.0.

More particularly, the pharmaceutical compositions of the inventioncomprise a therapeutically or prophylactically effective amount of oneor more compound of the present invention, together with one or morepharmaceutically acceptable excipients. A therapeutically orprophylactically effective amount of a compound of the present inventionincludes a viral inhibitory amount of said compound or an amounteffective for affecting viral IRES activity. By “viral inhibitoryamount” it is meant an amount sufficient to inhibit viral replication orinfectivity. By “an amount effective for affecting viral IRES activity”it is meant an amount sufficient to inhibit viral IRES mediatedinitiation and/or translation. Optionally, the pharmaceuticalcompositions of the invention may comprise a combination of compounds ofthe present invention, or may include a second active ingredient usefulin the treatment of viral infections, such as anti-viral agents thatinclude, but are not limited to: pegylated interferon, including by wayof non-limiting example pegylated α-interferon; un-pegylated interferon,including by way of non-limiting example, un-pegylated α-interferon;ribavirin or prodrugs or derivatives thereof; a glucosidase inhibitor;protease inhibitors; polyermase inhibitors; p7 inhibitors; entryinhibitors, including fusion inhibitors such as Fuzeon (Trimeris);helicase inhibitors; a Toll-like receptor agonist, a caspase inhibitor,anti-fibrotics; drugs that target IMPDH (inosine monophosphatedehydrogenase inhibitors), such as Merimepadib™ (Vertex PharmaceuticalsInc.); synthetic thymosin alpha 1 (ZADAXIN™, SciClone PharmaceuticalsInc.); a glycosidase inhibitor; therapeutic viral vaccines, such asthose produced by Chiron and Immunogenics; and immunomodulators, such ashistamine.

Formulations of the present invention, e.g., for parenteral or oraladministration, are most typically solids, liquid solutions, emulsionsor suspensions, while inhaleable formulations for pulmonaryadministration are generally liquids or powders, with powderformulations being generally preferred. A preferred pharmaceuticalcomposition of the invention may also be formulated as a lyophilizedsolid that is reconstituted with a physiologically compatible solventprior to administration. Alternative pharmaceutical compositions of theinvention may be formulated as syrups, creams, ointments, tablets, andthe like.

The term “pharmaceutically acceptable excipient” refers to an excipientfor administration of a pharmaceutical agent, such as the compounds ofthe present invention. The term refers to any pharmaceutical excipientthat may be administered without undue toxicity. Pharmaceuticallyacceptable excipients are determined in part by the particularcomposition being administered, as well as by the particular method usedto administer the composition. Accordingly, there exists a wide varietyof suitable formulations of pharmaceutical compositions of the presentinvention (see, e.g., Remington's Pharmaceutical Sciences).

Suitable excipients may be carrier molecules that include large, slowlymetabolized macromolecules such as proteins, polysaccharides, polylacticacids, polyglycolic acids, polymeric amino acids, amino acid copolymers,and inactive virus particles. Other exemplary excipients includeantioxidants such as ascorbic acid; chelating agents such as EDTA;carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid; liquids such as oils, water,saline, glycerol and ethanol; wetting or emulsifying agents; pHbuffering substances; and the like. Liposomes are also included withinthe definition of pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be formulated inany form suitable for the intended method of administration. Whenintended for oral use for example, tablets, troches, lozenges, aqueousor oil suspensions, non-aqueous solutions, dispersible powders orgranules (including micronized particles or nanoparticles), emulsions,hard or soft capsules, syrups or elixirs may be prepared. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents including sweetening agents,flavoring agents, coloring agents and preserving agents, in order toprovide a palatable preparation.

Pharmaceutically acceptable excipients particularly suitable for use inconjunction with tablets include, for example, inert diluents, such ascelluloses, calcium or sodium carbonate, lactose, calcium or sodiumphosphate; disintegrating agents, such as croscarmellose sodium,cross-linked povidone, maize starch, or alginic acid; binding agents,such as povidone, starch, gelatin or acacia; and lubricating agents,such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample celluloses, lactose, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with non-aqueousor oil medium, such as glycerin, propylene glycol, polyethylene glycol,peanut oil, liquid paraffin or olive oil.

In another embodiment, pharmaceutical compositions of the invention maybe formulated as suspensions comprising a compound of the presentinvention in an admixture with at least one pharmaceutically acceptableexcipient suitable for the manufacture of a suspension. In yet anotherembodiment, pharmaceutical compositions of the invention may beformulated as dispersible powders and granules suitable for preparationof a suspension by the addition of suitable excipients.

Excipients suitable for use in connection with suspensions includesuspending agents, such as sodium carboxymethylcellulose,methylcellulose, hydroxypropyl methylcelluose, sodium alginate,polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wettingagents such as a naturally occurring phosphatide (e.g., lecithin), acondensation product of an alkylene oxide with a fatty acid (e.g.,polyoxyethylene stearate), a condensation product of ethylene oxide witha long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), acondensation product of ethylene oxide with a partial ester derived froma fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitanmonooleate); and thickening agents, such as carbomer, beeswax, hardparaffin or cetyl alcohol. The suspensions may also contain one or morepreservatives such as acetic acid, methyl and/or n-propylp-hydroxy-benzoate; one or more coloring agents; one or more flavoringagents; and one or more sweetening agents such as sucrose or saccharin.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth;naturally occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids; hexitol anhydrides, such assorbitan monooleate; and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

Additionally, the pharmaceutical compositions of the invention may be inthe form of a sterile injectable preparation, such as a sterileinjectable aqueous emulsion or oleaginous suspension. This emulsion orsuspension may be formulated according to the known art using thosesuitable dispersing or wetting agents and suspending agents which havebeen mentioned above. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, such as a solution in 1,2-propane-diol.The sterile injectable preparation may also be prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution, and isotonic sodium chloride solution. Inaddition, sterile fixed oils may be employed as a solvent or suspendingmedium. For this purpose any bland fixed oil may be employed includingsynthetic mono- or di-glycerides. In addition, fatty acids such as oleicacid may likewise be used in the preparation of injectables.

Generally, the compounds of the present invention useful in the methodsof the present invention are substantially insoluble in water and aresparingly soluble in most pharmaceutically acceptable protic solventsand in vegetable oils. However, the compounds are generally soluble inmedium-chain fatty acids (e.g., caprylic and capric acids) ortriglycerides and have high solubility in propylene glycol esters ofmedium-chain fatty acids. Also contemplated in the invention arecompounds which have been modified by substitutions or additions ofchemical or biochemical moieties which make them more suitable fordelivery (e.g., increase solubility, bioactivity, palatability, decreaseadverse reactions, etc.), for example by esterification, glycosylation,PEGylation, etc.

In a preferred embodiment, the compounds of the present invention may beformulated for oral administration in a lipid-based formulation suitablefor low solubility compounds. Lipid-based formulations can generallyenhance the oral bioavailability of such compounds. As such, a preferredpharmaceutical composition of the invention comprises a therapeuticallyor prophylactically effective amount of a compound of the presentinvention, together with at least one pharmaceutically acceptableexcipient selected from the group consisting of: medium chain fattyacids or propylene glycol esters thereof (e.g., propylene glycol estersof edible fatty acids such as caprylic and capric fatty acids) andpharmaceutically acceptable surfactants such as polyoxyl 40 hydrogenatedcastor oil.

In an alternative preferred embodiment, cyclodextrins may be added asaqueous solubility enhancers. Preferred cyclodextrins includehydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosylderivatives of α-, β-, and γ-cyclodextrin. A particularly preferredcyclodextrin solubility enhancer is hydroxypropyl-β-cyclodextrin (HPBC),which may be added to any of the above-described compositions to furtherimprove the aqueous solubility characteristics of the compounds of thepresent invention. In one embodiment, the composition comprises 0.1% to20% hydroxypropyl-β-cyclodextrin, more preferably 1% to 15%hydroxypropyl-β-cyclodextrin, and even more preferably from 2.5% to 10%hydroxypropyl-β-cyclodextrin. The amount of solubility enhancer employedwill depend on the amount of the compound of the present invention inthe composition.

F. Combination Therapy

It is also possible to combine any compound of the present inventionwith one or more other active ingredients useful in the treatment of HCVinfection, including compounds, in a unitary dosage form, or in separatedosage forms intended for simultaneous or sequential administration to apatient in need of treatment. When administered sequentially, thecombination may be administered in two or more administrations. In analternative embodiment, it is possible to administer one or morecompounds of the present invention and one or more additional activeingredients by different routes.

The skilled artisan will recognize that a variety of active ingredientsmay be administered in combination with the compounds of the presentinvention that may act to augment or synergistically enhance the viralinhibiting activity of the compounds of the invention. Such activeingredients include anti-HCV agents. Anti-HCV agents include agents thattarget the virus as well as agents that have an immunomodulatory effect.For example, anti-HCV agents include, but are not limited to,interferon, including, for example without limitation, IFN-α, ribavirinor prodrugs or derivatives thereof; a glucosidase inhibitor, proteaseinhibitors, polymerase inhibitors, helicase inhibitors, a Toll-likereceptor agonist, a caspase inhibitor and a glycosidase inhibitor.Furthermore, the compounds of the invention may also be administered incombination with other compounds that affect IRES activity known to oneof skill in the art.

According to the methods of the invention, the combination of activeingredients may be: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by any other combinationtherapy regimen known in the art. When delivered in alternation therapy,the methods of the invention may comprise administering or deliveringthe active ingredients sequentially, e.g., in separate solution,emulsion, suspension, tablets, pills or capsules, or by differentinjections in separate syringes. In general, during alternation therapy,an effective dosage of each active ingredient is administeredsequentially, i.e., serially, whereas in simultaneous therapy, effectivedosages of two or more active ingredients are administered together.Various sequences of intermittent combination therapy may also be used.

To assist in understanding the present invention, the following Examplesare included. The experiments relating to this invention should not, ofcourse, be construed as specifically limiting the invention and suchvariations of the invention, now known or later developed, which wouldbe within the purview of one skilled in the art are considered to fallwithin the scope of the invention as described herein and hereinafterclaimed.

EXAMPLES

The present invention is described in more detail with reference to thefollowing non-limiting examples, which are offered to more fullyillustrate the invention, but are not to be construed as limiting thescope thereof. The examples illustrate the preparation of certaincompounds of the invention, and the testing of these compounds in vitroand/or in vivo. Those of skill in the art will understand that thetechniques described in these examples represent techniques described bythe inventors to function well in the practice of the invention, and assuch constitute preferred modes for the practice thereof. However, itshould be appreciated that those of skill in the art should in light ofthe present disclosure, appreciate that many changes can be made in thespecific methods that are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the invention.

Example 1 Preparation of Compounds of the Invention Example 1APreparation of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (compound 5)

Step A: A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120mL) was cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72mL, 88.4 mmol). After the addition, the reaction mixture was stirred atthis temperature for 1 h. The dark solution was poured into ice water(600 mL) and the light brown solid was collected by filtration, washedwith additional H₂O and dried to afford 9.9 g (85%) of6-methoxy-1H-indole-3-carbonitrile as a light brown solid.

Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6mmol) in DMF (150 mL) was added NaH (60% dispersion in mineral oil, 3.45g, 86.3 mmol). The reaction mixture was stirred for 15 min and thenethyl iodide (5.53 mL, 69.1 mmol) was added and the mixture was stirredat room temperature overnight. The reaction mixture was then dilutedwith H₂O and extracted with EtOAc (2×). The organic phases were washedwith H₂O (3×) and saturated NaCl and then dried and concentrated to asemi-solid. The crude product was purified via column chromatography onsilica gel (200 g) using CH₂Cl₂/hexanes (50-100%) as eluent to yield6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.

Utilizing steps A and B above and substituting different indoles andalkyl halides gave the following compounds: Compounds 43, 45, 51, 52,108, 109, 115, 118, 120, 123, 126, 179 and 714.

Example 1B Preparation of 6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(compound 9)

Step A: To a solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile(2.85 g, 14.2 mmol), prepared by example 1A, step B, in CH₂Cl₂ (40 mL)was added a 1M solution of BBr₃ in CH₂Cl₂ (28.5 mL, 28.5 mmol) at 0° C.The mixture was allowed to warm to room temperature and kept for 2.5 h.The dark reaction mixture was then poured onto ice and sufficient 1MNaOH was added until the pH was 8-9. The product was extracted withCH₂Cl₂ (3×) and the combined organic phases were washed with saturatedNaHCO_(3 , H) ₂O and saturated NaCl. After drying over MgSO₄, thesolution was concentrated and the product was purified by chromatography(EtOAc/CH₂Cl₂, 0-10%) to afford 2.15 g (82%) of6-hydoxy-1-ethyl-1H-indole-3-carbonitrile as a yellow solid.

Step B: To a solution 6-hydoxy-1-ethyl-1H-indole-3-carbonitrile (80 mg,0.43 mmol) in 5 mL of methyl ethyl ketone was added anhydrous K₂CO₃ (71mg, 0.52 mmol) and iodomethane (0.05 mL, 0.60 mmol). After stirringovernight at reflux, the reaction mixture was cooled, diluted with H₂Oand extracted with EtOAc (3×). The combined organic phases were driedand concentrated. Flash chromatography (CH₂Cl₂) gave 94 mg (100%) of6-ethoxy-1-ethyl-1H-indole-3-carbonitrile as a white wax.

In similar fashion, following steps A and B, above, the followingcompounds were also prepared: compounds 6, 10, 11, 12 and 24

Example 1C Preparation of5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile(compound 44)

A mixture of p-iodoanisole (85 mg, 0.36 mmol), anhydrous K₃PO₄ (102 mg,0.48 mmol), CuI (4.6 mg, 0.024 mmol) and N,N′-Dimethylcyclohexane-1,2-diamine (14 mg, 0.096 mmol) was added to5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile (45 mg, 0.24 mmol), preparedas described by the method of example 1A, step A, in anhydrous toluene(0.4 mL). After heating at reflux for 24 h, the solvent was evaporatedunder vacuum. The residue was dissolved with CH₂Cl₂ (5 mL) and themixture was filtered. The filtrate was concentrated to afford crudeproduct, which was purified by silica gel chromatography usingEtOAc/petroleum ether (1:4) as eluent to yield5-(4-methoxyphenyl)-5H-[1,3]dioxolo[4,5-f]indole-7-carbonitrile.

Utilizing the procedure above and substituting different aryl iodidesgave the following compounds: compounds 4, 8, 102, 103, 111, 112, 117,119, 124, 125, 127, 154.

Example 1D Preparation of1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile (compound 13)

To a solution of 1-ethyl-6-hydroxy-1H-indole-3-carbonitrile (60 mg, 0.32mmol) prepared as described in example 1A, step A, in DMF (5 mL) wasadded K₂CO₃ (55 mg, 0.40 mmol) and 2-chloropyridazine (45 mg, 0.40mmol). The mixture was heated at 110° C. for 18 h. After cooling to roomtemperature, the reaction mixture was diluted with H₂O and extractedwith EtOAc (3×). The combined organic phases were washed with H₂O andsaturated NaCl, dried and concentrated. The product was isolated bychromatography (EtOAc/CH₂Cl₂, 1-3%) over silica gel to afford 76 mg(96%) of the title compound,1-ethyl-6-(pyrazin-2-yloxy)-1H-indole-3-carbonitrile, as an off-whitesolid.

Example 1E Preparation of 3-cyano-1-ethyl-1H-indole-6-carboxylic acidphenylamide (compound 15)

Step A: A solution of methyl 3-cyano-1-ethyl-1H-indole-6-carboxylate(1.60 g, 7.02 mmol), prepared by the method described in example 1A frommethyl 1H-indole-6-carboxylate, in THF (35 mL) was treated with 1N NaOH(7.7 mL, 7.7 mmol) and heated at reflux for 2.5 h. After cooling to roomtemperature, most of the THF was removed and the solution was dilutedwith H₂O and extracted with ether (2×). The ether extracts werediscarded. The aqueous phase was then acidified with 6N HCl to pH 2 andthen extracted with EtOAc (3×). The EtOAc layers were combined, washedwith saturated NaCl and then dried and concentrated to afford 1.43 g(95%) of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid as a white solid.

Step B: A suspension of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid(0.42 g, 1.96 mmol) in CH₂Cl₂ (15 mL) was cooled to 0° C. The suspensionwas treated with DMF (2 drops) and then oxalyl chloride (0.34 mL, 3.92mmol) was added via syringe during 2 minutes after which the ice bathwas removed and the reaction mixture was allowed to warm to ambienttemperature during 1.5 h during which time the reaction became a yellowsolution. The solution was then concentrated in vacuo to afford 0.46 g(quantitative yield) of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride asa yellow solid.

Step C: A suspension of 3-cyano-1-ethyl-1H-indole-6-carbonyl chloride(70 mg, 0.30 mmol) in THF (5 mL) was cooled to 0° C. and treated withaniline (0.08 mL, 0.90 mmol). After the addition the reaction was warmedto ambient temperature and after stirring for an additional 16 hours,the reaction mixture was diluted with H₂O and extracted with EtOAc (2×).The combined organic phases were washed with saturated NaCl and thendried and concentrated to afford the product. Chromatography(EtOAc/CH₂Cl₂, 2/98) over silica gel gave 44 mg (51%) of3-cyano-1-ethyl-1H-indole-6-carboxylic acid phenylamide.

Utilizing essentially the procedure above gave the following compound:Compound 89.

Example 1F Preparation of t-butyl(3-cyano-1-ethyl-1H-indol-6-yl)-carbamate (compound 16)

A solution of 3-cyano-1-ethyl-1H-indole-6-carboxylic acid (0.60 g, 2.80mmol) from Example 1E, step A, in t-butanol (20 mL) was treated withEt₃N (0.46 mL, 3.36 mmol) and diphenylphosphoryl azide (0.73 mL, 3.36mmol) and then heated at reflux for 4 h. After cooling to roomtemperature, most of the t-butanol was removed in vacuo to give an oil,which was then dissolved in EtOAc. After washing with H₂O, the organicphase was back-extracted with EtOAc and the organic layers were combinedand washed sequentially with additional H₂O, saturated NaHCO₃ andsaturated NaCl. The organic phase was dried, concentrated and theresulting crude product was purified by chromatography over silica gelusing EtOAc/CH₂Cl₂ (0-1%) to afford 0.52 g (65%) of t-butyl(3-cyano-1-ethyl-1H-indol-6-yl)-carbamate as a white solid.

The following compound was made in similar fashion: compound 90.

Example 1Ga Preparation of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile via Suzukiroute (compound 55)

Step A: A 2M solution of lithium diisopropyl amide in THF/hexanes(Acros) (3.9 mL, 7.8 mmol) was diluted with THF (5 mL) in a flame-driedflask. After cooling the reaction to −30° C., a solution of1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.30 g, 6.5 mmol) in THF (10mL) was added dropwise during 10 min, maintaining the temperature at−30° C. After stirring for an additional 30 min at this temperature, asolution of iodine (2.31 g, 9.1 mmol) in THF (5 mL) was added during 10min. After the addition, the reaction was warmed to ambient temperatureduring 1 h. The reaction was then diluted with ice-H₂O and extractedwith EtOAc (2×). The combined organic phases were washed with 1M sodiumthiosulfate and saturated NaCl and then concentrated to a brown solid.Chromatography (CH₂Cl₂/hexanes, 1/1) over silica gel gave 1.31 g (62%)of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile as an off-whitesolid.

Step B: A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile(1.25 g, 3.83 mmol),4-(4,4,5,5-tetramethyl)-1,3-2-dioxaboralanyl-2-yl-aniline (0.96 g, 4.90mmol), CsF (1.46 g, 9.58 mmol) and Pd(PPh₃)₂Cl₂ (110 mg, 0.15 mmol) inDME (20 mL) was added to a flask and alternatively evacuated and flushedwith N₂. The reaction was then heated at reflux for 24 h and then cooledto room temperature. The reaction mixture was diluted with H₂O andextracted with EtOAc (2×). The combined organic phases were washed withH₂O and saturated NaCl and then dried over MgSO₄ and concentrated. Thecrude reaction mix purified by flash chromatographt on silica gel usingEtOAc/CH₂Cl₂ (5/95) as eluent to afford 765 mg (69%) of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile as a yellowsolid.

Utilizing essentially the same procedure described above andsubstituting different boronic acids gave the following compounds:compounds 19, 20, 21, 22, 53, 63, 70, 71, 74, 76, 77, 79, 80, 100, 110,229, 239, 240, 247, 250, 254, 255, 256, 257, 258, 259, 260, 281, 282,283, 284, 286, 335, 336, 337, 338, 339, 347, 348, 426, 427, 428, 429,476, 543, 578, 758.

Example 1Gb Preparation of2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile viaalternative Suzuki route

To a solution of (i-Pr)₂NH (1.35 mL, 9.65 mmol) in THF (30 mL) cooled to−78° C. was added n-BuLi (3.7 mL, 2.5M in hexanes, 9.21 mmol) in oneportion. The acetone/dry ice bath was exchanged for ice/water bath andthe solution was stirred further for 40 min. The solution was cooled to−78° C. and solution of 1-butyl-6-methoxy-1H-indole-3-carbonitrile,prepared as in example 1A (2.0 g, 8.77 mmol) in THF (10 mL) was addeddropwise. This solution was stirred for 15 min at −78° C., following by20 min at −20° C. Trimethyl borate (1.0 mL, 8.77 mmol) was added, thereaction mixture was stirred for 15 min at −20° C. after which thecooling bath was removed and this solution was stirred further at roomtemperature for 1 h. A solution of K₃PO₄ was added (11.7 mL, 3M aqueoussolution, 35.1 mmol) followed by a solution of 4-iodoaniline (2.5 g,11.40 mmol) and PdCl₂dppf catalyst (640 mg, 0.88 mmol) in DMF (40 mL,plus a 5 mL rinse). The reaction mixture was stirred overnight (ca. 18h.) and then water (80 mL) was added and the product was extracted withEtOAc (3×50 mL). The combined organic fractions were dried over MgSO₄,filtered and concentrated under reduced pressure. The crude product waspurified via flush chromatography on silica gel (5→60% EtOAc/Hexanes aseluant) to afford the desired2-(4-aminophenyl)-1-butyl-6-methoxy-1H-indole-3-carbonitrile as a tansolid (2.4 g, 86% yield).

The following compounds were prepared in similar fashion utilizing otherindole and aryl and hereroaryl bromides and iodides: Compounds 656, 659,660, 661, 682, 683, 712, 731, 732, 733, 806, 807, 808, 809, 810, 811,812, 813, 814, 827.

Example 1Gc Preparation of2-(4-aminophenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile viaNegishi route.

A nitrogen-purged flask fitted with a septum and a nitrogen needle wascharged with dry THF (all additions performed by syringe) (20 mL).Diisopropylamine (Aldrich Sure-Seal, 2.00 mL, 14.3 mmol) was added, andthe solution was cooled to 0° C. n-Butyllithium (8.50 mL of 1.6 Msolution in hexane, 13.6 mmol) was added slowly. The flask was allowedto warm to room temperature briefly, and then was cooled to −78° C. Aconcentrated THF solution of 6-methoxy-1-propyl-1H-indole-3-carbonitrile(2.77 g, 12.9 mmol; prepared analogously to compound 5 of Example 1A)was added slowly, and the resulting solution was maintained at −78° C.for 30 min. The flask was then transferred to a water-ice bath andallowed to come to 0° C. for about 15 minutes. The solution was onceagain cooled to −78° C., and ZnCl₂ (0.5 M solution in THF, 27.0 mL, 13.5mmol) was slowly added. A precipitate was observed at this point, whichmay have been the bis(indole)zinc compound, but the solution becamehomogeneous when the entire volume of zinc chloride solution was added.After about 10 minutes, the solution was allowed to come to roomtemperature, and a THF solution (5 mL) of 4-iodoaniline (3.47 g, 15.8mmol) and triphenylphosphine (338 mg, 1.29 mmol) was added. The septumwas removed, and solid Pd₂(dba)₃ (295 mg, 0.322 mmol) was added. Areflux condenser was fitted to the flask, and the solution was degassedby three successive cycles of vacuum pumping/N₂ purging. The solutionwas then heated to reflux overnight. After cooling to room temperature,the solution was poured into 4 volumes of water, and 4 volumes of ethylacetate were added. The resulting mixture was vigorously stirred for 30minutes, then filtered through celite (with ethyl acetate washing) toremove solid Zn-and Pd-containing material. The phases were separated,and the aqueous phase was extracted with more ethyl acetate. The organicphases were washed in sequence with saturated brine, combined, driedover anhydrous sodium sulfate, filtered and evaporated. A solidprecipitate formed at this point, which was sufficiently pure productand was collected by trituration with ether and filtration. Theremaining material was purified by column chromatography (eluting 1:2ethyl acetate-hexane on silica gel 60). Total yield of the product,2-(4-amino-phenyl)-6-methoxy-1-propyl-1H-indole-3-carbonitrile, was 2.75g (8.99 mmol, 70%).

The following compounds were made using essentially the same procedureand substituting other aryl or heteroaryl iodides or bromides: Compounds393, 408, 430, 431, 436, 437, 438, 459, 460, 461, 462, 483, 484, 632,633, 634, 635, 636, 650, 651.

Example 1Gd Preparation of1-ethyl-2-(3-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile (Compound288)

Step A: A solution of THF (60 mL) and diisopropylamine (5.5 mL, 39 mmol)was cooled to −78° C. n-Butyllithium (14.5 mL, 2.5M in hexanes, 36.2mmol) was added dropwise over 5 minutes. The LDA mixture was stirred at−78° C. for 10 minutes, and then at 0° C. for 20 minutes. The solutionwas re-cooled to −78° C. 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (5.0g, 25 mmol), prepared as in example 1A, was taken up in THF (30 mL) andadded dropwise to the LDA mixture over 15 minutes. The reaction wasstirred at −78° C. for 10 minutes, and at 0° C. for 30 minutes. Onceagain, the reaction mixture was cooled to −78° C. Tributyltin iodide (10mL, 35 mmol) was added dropwise. This was stirred at −78° C. for 15minutes, and then at 0° C. for 30 minutes. The reaction mixture wasabsorbed onto silica gel and concentrated. Purification bychromatography (CH₂Cl₂) yielded1-ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile (12.05 g,98%).

Step B: 1-Ethyl-6-methoxy-2-tributylstannanyl-1H-indole-3-carbonitrile(1.0 g, 2.05 mmol), prepared in step A, was combined with 3-iodophenol(474 mg, 2.15 mmol), Pd(PPh₃)₂Cl₂ (67 mg, 0.102 mmol), CuI (75 mg, 0.39mmol) and THF (4.0 mL). This mixture was heated at 65° C. overnight. Thereaction mixture was diluted in EtOAc, and was filtered through celite.The filtrate was concentrated and the residue was purified by silica gelchromatography (4:1, CH₂Cl₂/EtOAc) to yield crude product. Ethertrituration yielded1-ethyl-2-(3-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (430 mg,72%) as a yellow-white solid.

The following compounds were prepared similarly as above, using othercommercially available iodides and bromides, or using iodides derivedfrom a one step amidation of p-iodophenylsulfonyl chloride: Compounds275, 276, 277, 278, 331, 363, 364, 373, 374, 375, 474, 475, 678.

Example 1Ge Preparation of ethanesulfonic acid[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide viaHeck route (compound 519)

Step A: A solution of 6-difluoromethoxy-1-ethyl-1H-indole (402.8 mg,2.04 mmol), ethanesulfonic acid (4-iodo-phenyl)-amide (712.1 mg, 2.29mmol), cesium carbonate (733.2 mg, 3.82 mmol), triphenylphosphine (33.1mg, 0.13 mmol) and palladium acetate (5.7 mg, 0.025 mmol) in DMA (5 ml)was heated to 135° C. for 48 h. The reaction mixture was diluted withwater and extracted with EtOAc (2×10 mL). The combined organic phaseswere washed with brine, dried over MgSO₄, and then concentrated. Theresidue was purified via column chromatogrphy on silica gel (25 g) usingEtOAc/Hexanes (10-20%) as eluent to afford 298.2 mg (37.1% yield) ofethanesulfonic acid[4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide, compound 516,as a light brown solid.

Step B: Following the procedure 1A, step A, ethanesulfonic acid[4-(6-difluoromethoxy-1-ethyl-1H-iodo-2-yl)-phenyl]-amide was convertedto ethanesulfonic acid[4-(3-cyano-6-difluoromethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-amide,compound 519.

Following steps A and B above, the following compounds were prepared insimilar fashion: Compounds 343, 344, 345, 346, 409, 410, 411, 412, 413,414, 415, 416, 417, 418, 419, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 473, 515, 517, 518, 520, 521, 522, 523, 524, 575, 577, 579,580, 611, 612, 613, 614

Example 1H Preparation of1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile(compound 67)

A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg,0.46 mmol), prepared as described in example 1Ga, step A,4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine)palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol)was added to a sealable tube and alternatively evacuated and flushedwith N₂. To the tube was then added DMF (4 mL) and Et₃N (0.25 mL, 1.84mmol) and the reaction was heated at 80° C. for 20 h and then cooled toroom temperature. The reaction mixture was diluted with H₂O andextracted with EtOAc (2×). The combined organic phases were washed withH₂O (3×) and saturated NaCl and then dried over MgSO4 and concentrated.The crude reaction mix was absorbed on silica gel (0.6 g) andchromatographed over silica gel using EtOAc/hexanes (10-20%) as eluentto afford 120 mg (82%) of1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile asa yellow solid.

Utilizing essentially the same procedure described above andsubstituting different acetylene derivatives gave the followingcompounds: compounds 64, 65, 66, 68, 69, 91, 92, 93, 94, 95, 96, 133,134, 135, 136, 137, 143, 144, 145, 146, 147, 148, 149, 150, 151, 158,159, 160, 161, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 184,185, 186, 187, 188, 196, 197, 198, 199, 200, 201, 202, 223, 230, 231,232, 233, 234, 235, 236, 237, 238.

Example 1I Preparation of1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole (compound28)

Step A: A solution of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00g, 5.00 mmol) in MeOH (10 mL) was treated with a 50% aqueous solution ofhydroxylamine (0.38 mL, 6.25 mmol) and heated at reflux for 18 h. Aftercooling to room temperature, the heterogeneous mixture was filtered toafford 525 mg of desired product as a tan solid. The filtrate wasconcentrated to an oil, which was then dissolved in CH₂Cl₂ andchromatographed over silica gel using EtOAc/CH₂Cl₂ (15-50%) to afford anadditional 295 mg of product as a tan solid. Total yield of1-ethyl-N-hydroxy-6-methoxy-1H-indole-3-carboxamidine was 820 mg (70%).

Step B: The N-hydroxycarboxamidine above (50 mg, 0.21 mmol),polystyrene-diisopropylethylamine 165 mg, 3.90 mmol/g loading) andpropionyl chloride (0.03 mL, 0.32 mmol) in CH₂Cl₂ (10 mL) were placed ina tube and rotated for 22 h at room temperature. After this time,trisamine resin (77 mg, 2.71 mmol/g loading) was then added and the tuberotated for an additional 30 min at room temperature. Solids werefiltered and then the filtrate was concentrated and diluted with toluene(5 mL) and heated at 110° C. overnight. The crude reaction mixture wasconcentrated and purified by chromatography (EtOAc/CH₂Cl₂, 2/98) toafford 27 mg (46%) of1-ethyl-3-(5-ethyl-[1,2,4]oxadiazol-3-yl)-6-methoxy-1H-indole as a whitesolid.

The following compound was prepared utilizing the above procedure withsubstitution of the appropriate acyl halide: compound 29.

Example 1J Preparation of1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole (compound54)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.00 g,5.00 mmol) in toluene (30 mL) was treated with triethylaminehydrochloride (1.03 g, 7.50 mmol) and sodium azide (0.49 g, 7.50 mmol)and was heated at reflux for 16 h. After cooling to room temperature,the reaction mixture was diluted with saturated NaHCO₃ and extractedwith EtOAc. The organic layer was then washed with additional NaHCO₃(2×). The combined aqueous phases were acidified to pH 2 with 6N HCl.The resultant thick precipitate was extracted with hot EtOAc (3×) andthe combined organic phases were washed with saturated NaCl and driedand concentrated to give 0.55 g (45%) of1-ethyl-6-methoxy-3-(1H-tetrazol-5-yl)-1H-indole as a yellow solid.

Step B: A suspension of the tetrazole above (50 mg, 0.21 mmol) andpropionyl chloride (0.03 mL, 0.31 mmol) in dichloroethane (5 mL) washeated at reflux for 21 h. After cooling the reaction mixture to roomtemperature, polystyrene trisamine resin (70 mg, 3.4 meq/g) was addedand the reaction was rotated for 4 h at room temperature. Afterfiltering off the resin, and removal of the solvent, the crude productwas absorbed on silica gel and the product was isolated by silica gelchromatography (EtOAc/CH₂Cl₂, 5-10%) to afford 30 mg (53%) of1-ethyl-6-methoxy-3-(5-ethyl-[1,3,4]oxadiazol-2-yl)-1H-indole as a tansolid.

Example 1K Preparation of ethyl5-difluoromethoxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate(compound 49)

Freon-22 (HCF₂Cl) gas was bubbled into a solution of ethyl5-hydroxy-1-(4-methoxyphenyl)-2-methyl-1H-indole-3-carboxylate (250 mg,0.77 mmol) in CH₂Cl₂ (5 mL) at 0° C. containing a small amount oftetrabutylammonium bromide as a phase transfer catalyst. A 50% solutionof NaOH was added dropwise at 0° C. After the addition, the mixture wasstirred at 0° C. for 2 h. After the addition of H₂O, the organic phasewas separated and washed with brine and dried over Na₂SO₄. The solventwas then concentrated and the residue was purified by columnchromatography over silica gel using EtOAc/petroleum ether (1/2) aseluent to yield the desired product in 40% yield.

The following compounds were prepared utilizing the above procedure withsubstitution of the appropriate hydroxyindole: compounds 18, 46, and 50.

Example 1L Preparation of1-[5-methoxy-1-(4-methoxyphenyl)-1-H-indol-3-yl]-ethanone (compound 42)

5-Methoxy-1-(4-methoxyphenyl)-1-H-indole (50 mg, 0.2 mmol), prepared bythe method of example 1C, was dissolved in 1 mL of CH₂Cl₂ at 0° C.Et₂AlCl (300 μL, 1M in hexanes, 0.3 mmol) was then added. After stirringat 0° C. for 30 min, a solution of acetyl chloride (22 μL, 0.3 mmol) in1 mL of CH₂Cl₂ was added dropwise. This was stirred at 0° C. for afurther 90 min. The reaction mixture was quenched with H₂O and wasextracted with CH₂Cl₂ and concentrated in vacuo. Purification by columnchromatography on silica gel EtOAc/CH₂Cl₂ (5/95) yielded the titlecompound as a white solid (42 mg, 71%).

Utilizing essentially the same procedure described above andsubstituting different acyl chlorides, the following compounds wereprepared: compounds 32, 33, 34, 37, 38, 39, 47, 48.

Example 1M Preparation of 1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole(compound 57)

Step A: A mixture of 1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone (200mg, 0.92 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by theprocedure described in example 1L, hydroxylamine hydrochloride (128 mg,1.84 mmol), NaOAc (151 mg, 1.84 mmol) and EtOH (7 mL) was heated at 85°C. for 4 h. The reaction mixture was then partitioned between H₂O andEtOAc. The organic phase was dried and concentrated in vacuo.Purification by column chromatography using EtOAc/CH₂Cl₂ (1/9) yielded1-(1-ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime as a white solid(189 mg, 92%).

Step B: 1-(1-Ethyl-6-methoxy-1-H-indole-3-yl)ethanone oxime (100 mg,0.43 mmol) was dissolved in THF (900 μL) at 0° C. n-BuLi (450 μL, 2.5 Min hexanes, 1.12 mol) was added dropwise, resulting in instantprecipitation of solids. DMF (70 μL, 0.9 mol) in 260 μL of was thenadded dropwise. This was stirred at 0° C. for 1 h, then at roomtemperature for 1 h. The reaction mixture was pipetted into a mixturecontaining 1 mL of H₂O, 1 mL of THF, and 100 μL of concentrated H_(2 SO)₄. This mixture was heated at 75° C. for 1 h and then was partitionedbetween H₂O and EtOAc. The organic phase was dried and concentrated.Purification by column chromatography (CH₂Cl₂) yielded1-ethyl-3-isoxazol-3-yl-6-methoxy-1-H-indole product as a white solid(13 mg, 12%).

Example 1N Preparation of 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole(compound 58)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)ethanone (100 mg, 0.46 mmol),prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described inexample 1L, was heated with 1.5 mL of dimethylformamide dimethylacetaland 100 μL of pyrrolidine at 110° C. overnight. The dimethylformamidedimethylacetal was then concentrated in vacuo. The residue wasredissolved in 1.25 mL of EtOH and 250 μL of H₂O, and was treated withhydroxylamine hydrochloride (66 mg, 0.95 mmol) and heated at 80° C. for2 h. Partitioning between H₂O and EtOAc and drying and concentration ofthe organic phase followed by purification by silica gel chromatography(EtOAc/CH₂Cl₂, 5/95) gave 1-ethyl-3-isoxazol-5-yl-6-methoxy-1H-indole asa white solid (72 mg, 66%).

Utilizing essentially the same procedure described above, the followingcompound was prepared: Compound 60.

Example 1O Preparation of1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (compound 59)

1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol),prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described inexample 1L, was heated with 1.5 mL of dimethylformamide dimethyl acetaland 100 μL pyrrolidine at 110° C. overnight. The DMF dimethyl acetal wasremoved in vacuo. The residue was redissolved in 3 mL of acetic acid,hydrazine hydrate (70 μL, 1.38 mmol) was added, and the mixture washeated to 100° C. for 2 h. The acetic acid was removed in vacuo, and theresidue was partitioned between EtOAc and saturated NaHCO₃. The organicphase was dried and concentrated and the product purified by silica gelchromatography (EtOAc/Hex, 1/1) to give 59 mg of1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorlesssemisolid. Trituration in Et₂O gave a white crystalline powder.

The following compound was prepared utilizing the above procedure:Compound 61.

Example 1P Preparation of methyl1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (compound 72)

Step A: 1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45mmol) was dissolved in DMF (3.3 mL). This was added dropwise to anice-cold solution of POCl₃ (430 μL, 4.5 mmol) in DMF (1.5 mL). Thereaction mixture was stirred at room temperature for 90 minutes. Thereaction mixture was then treated with 6N NaOH (3.5 ml). The mixture wasthen partitioned between H₂O and ethyl acetate. Purification by silicagel chromatography (5-10% EtOAc/CH₂Cl₂) yielded1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%)as a white solid.

Step B: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (100mg, 0.42 mmol), TOSMIC (100 mg, 0.52 mmol), K₂CO₃ (178 mg, 1.29 mmol),and MeOH (800 μL) were heated at 80° C. overnight. The reaction mixturewas then partitioned between H₂O and ether. After drying andconcentrating the organic phase, the product was purified by silica gelchromatography (EtOAc/CH₂Cl₂, 10/90) to give methyl1-ethyl-3-oxazol-5-yl-1H-indole-6-carboxylate (26 mg, 23%) as anoff-white solid.

Example 1Q Preparation of methyl1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (compound 75)

Step A: 1-Ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (800mg, 3.5 mmol), prepared as shown in example 1P, step A, was dissolved inacetone (98 mL). A solution of KMnO₄ (655 mg, 4.15 mmol) in H₂O (31 mL)was added. The reaction mixture was stirred at room temperature for 90minutes. Another addition of KMnO₄ (108 mg) in H₂O (6 mL), followed bystirring for another 45 minutes was required to drive the reaction tocompletion. The reaction mixture was then quenched with 10% H₂O₂ (1.5mL). The mixture was filtered through celite. The filtrate was strippeddown under vacuum to roughly ⅓ of the volume. The residue was acidifiedwith 6N HCl, and was extracted into ethyl acetate. The solids isolatedfrom the ethyl acetate layer were triturated with acetone to yield1-ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (696 mg, 79%) asa light orange solid.

Step B: 1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg,2.43 mmol) was suspended in a solution of CH₂Cl₂ (27 ml) and DMF (20μL). Oxalyl chloride (470 μL, 5.38 mmol) was added, and the reactionmixture was stirred for 1 hour at room temperature. This mixture wasthen slowly poured into a rapidly stirring solution of concentratedNH₄OH (10 mL). This was then partitioned in H₂O and EtOAc. The residuefrom the ethyl acetate layer was triturated with acetone to yield6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as awhite solid.

Step C: A mixture of 150 mg (0.61 mmol) of6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide in diglyme (3.6 mL),and bromoacetaldehyde dimethyl acetal (430 μL, 3.7 mmol) was heated at125° C. for 2 h. The reaction mixture was cooled and partitioned in H₂Oand EtOAc. The organic phase was dried and concentrated and the productwas purified by silica gel chromatography (EtOAc/CH₂Cl₂ 5-10%). Theproduct containing fractions were combined and concentrated and thesolid was triturated with hexanes to yield methyl1-ethyl-3-oxazol-2-yl-1H-indole-6-carboxylate (75 mg, 46%) as a yellowsolid.

Example 1R Preparation of 1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole(compound 73)

Step A: 1-Ethyl-6-methoxy-1H-indole (900 mg, 5.14 mmol) was dissolved inDMF (1.5 mL). This was added dropwise to an ice-cold solution of POCl₃(500 μL, 5.2 mmol) in DMF (1.75 ml). After stirring at room temperaturefor 90 minutes, the reaction mixture was re-cooled in an ice bath andwas slowly quenched with 6N NaOH (4 mL). The reaction mixture waspartitioned between EtOAc and H₂O. Purification by silica gelchromatography (EtOAc/CH₂Cl₂, 5/95) yielded1-ethyl-6-methoxy-1H-indole-3-carbaldehyde (849 mg, 81%) as a yellowsolid.

Step B: 1-Ethyl-6-methoxy-1H-indole-3-carbaldehyde (600 mg, 2.95 mmol)was dissolved in acetone (85 mL). A solution of KMnO₄ (450 mg, 2.85mmol) in H₂O (28 mL) was added. This was stirred at room temperature for5 hours. Another solution of KMnO₄ (450 mg, 2.85 mmol) in H₂O (25 mL)was then added. After stirring for another hour at room temperature, thereaction was complete. The reaction mixture was quenched with 10% H₂O₂(1.5 mL), and was then filtered through celite. The filtrate wasstripped down under vacuum to roughly ⅓ of the volume. The residue wasacidified with 6N HCl, and was extracted into ethyl acetate.Purification by silica gel column (hexanes/acetone/acetic acid, 70/30/1)yielded crude product. Trituration with ether yielded pure1-ethyl-6-methoxy-1H-indole-3-carboxylic acid (365 mg, 56%) as a yellowsolid.

Step C: 1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14mmol) was suspended in a solution of CH₂Cl₂ (12.5 mL) and DMF (10 μL).Oxalyl chloride (230 μL, 2.64 mmol) was added, and the reaction mixturewas stirred for 1 hour at room temperature. This mixture was then slowlypoured into a rapidly stirring solution of concentrated NH₄OH (5 mL).This was then partitioned in H₂O and EtOAc. The residue from the ethylacetate layer was triturated with acetone to yield1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a whitesolid.

Step D: 1-Ethyl-6-methoxy-1H-indole-3-carboxamide (120 mg, 0.55 mmol),Lawesson's reagent (240 mg, 0.6 mmol), and toluene (2 mL) were heated at90° C. for 90 min. The reaction mixture was concentrated and purified bysilica gel chromatography (EtOAc/CH₂Cl₂, 1/9) to yield1-ethyl-6-methoxy-1H-indole-3-thiocarboxamide as a yellow solid (92 mg,71%).

Step E: 1-Ethyl-6-methoxy-1H-indole-3-thiocarboxamide (83 mg, 0.36mmol), glyme (3.6 mL) and bromoacetaldehyde dimethyl acetal (220 μL,1.86 mmol) were heated at 80° C. for 16 h. More bromoacetaldehydedimethyl acetal (250 μL was added. This was heated at 80° C. for 2 h.Addition of 250 μL more bromoacetaldehyde dimethyl acetal was followedby heating for another 2 hours. The reaction mixture was cooled to roomtemperature, absorbed onto silica and purified by silica gelchromatography (hexanes/EtOAc, 7/3) to afford1-ethyl-6-methoxy-3-thiazol-2-yl-1H-indole as a brown oil (44 mg, 47%).

The following compounds were prepared following the procedure describedabove: Compounds 78, 101, 104, 105 and 106.

Example 1S Preparation of1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile (compound 99)

Step A: To a suspension of LiAlH₄ (7.6 g, 0.2 mol) in dioxane (100 mL)was added dropwise a solution of methyl6-methoxy-1H-indole-2-carboxylate (8.2 g, 0.04 mol) in dioxane (50 mL)at 0° C. After the addition, the mixture was stirred at room temperaturefor 1 h and then heated at reflux for 5 h. After cooling to 0° C., thereaction was quenched by water (dropwise) and then 15% aqueous NaOH.After stirring at room temperature for 1 h, the mixture was filteredthrough Celite. The solid was washed with large amount of EtOAc. Thesolvent was washed with brine, dried over Na₂SO₄ and evaporated undervacuum. The residue was purified by flash column chromatography onsilica gel using EtOAc/petroleum ether (1/5) as eluent to yield 61% of6-methoxy-2-methyl-1H-indole.

Step B: To a solution of 6-methoxy-2-methyl-1H-indole (3.9 g, 24 mmol)in acetonitrile (200 mL) and DMF (20 mL) was added dropwise a solutionof ClSO₂NCO (4 mL, 1.3 eq.) in acetonitrile (31 mL) at 0° C. After theaddition, the mixture was stirred at room temperature for 3 h. Then itwas poured into ice water and saturated NaHCO₃ was added to it until itbecame basic. The aqueous phase was extracted with CH₂Cl₂ and thenevaporated. The residue was purified with flash column chromatography onsilica gel using EtOAc/petroleum ether (1/5) as eluent to yield 81% of6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step C: To a suspension of NaH (0.6 g, 2 eq.) in DMF (7 mL) was added asolution of 6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.3 g, 7.0mmol) in DMF (8 mL) followed by ethyl iodide (1.2 mL, 2 eq.) at 0° C.After stirring for 1 h, the mixture was poured into ice water and theextracted with CH₂Cl₂. The organic layer was washed with brine and driedwith Na₂SO₄. The solvent was evaporated under vacuum and purified withflash column chromatography on silica gel using EtOAc/petroleum ether(1/5) as eluent to yield 92% of1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile.

Step D: To a solution of1-ethyl-6-methoxy-2-methyl-1H-indole-3-carbonitrile (1.38 g, 6.45 mmol)in benzene (130 mL) was added benzoyl peroxide (226 mg) and NBS (1.21 g,1.05 eq.). Then the mixture was heated to reflux for 3 h. After coolingand filtering, the filtrate was concentrated under vacuum. The crude2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (1.6 g, 86%)was used without further purification.

Step E: To a solution of NaH (44 mg, 4 eq.) in DMF (0.5 mL) was added2-bromomethyl-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (80 mg, 0.274mmol) and phenol (2 eq.). After stirring for 20 h, the mixture waspoured into ice water and extracted with CH₂Cl₂. The organic layer waswashed with brine and dried with Na₂SO₄. The solvent was evaporatedunder vacuum and purified with flash column chromatography on silica gelusing EtOAc/petroleum ether (1/5) as eluent to yield1-ethyl-6-methoxy-2-phenoxymethyl-1H-indole-3-carbonitrile, compound 99.

Example 1T Preparation of 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile(compound 7)

Step A: A solution of 2-fluoro-5-nitroaniline (11.7 g, 74.9 mmol) indimethylformamide (120 mL) was treated with malononitrile (5.28 g, 80.0mmol) and potassium carbonate (11.05 g, 80.0 mmol) (Modification ofChem. Heterocyclic Cpd. (Engl. Trans., 9, 37 (2001). The resultingheterogeneous mixture was heated to gentle reflux for 3 h, then cooledand poured into water (500 mL). The resulting precipitate was collectedby filtration and taken up into ethyl acetate (300 mL). This solutionwas dried over Na₂SO₄, filtered and partially evaporated to give aprecipitate, which was collected by filtration. Further evaporation andfiltration gave a second crop. The two crops were combined and driedunder vacuum to give 2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile(7.90 g, 52%) as an orange powder.

Step B: A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg,1.79 mmol) in acetic acid (5 mL) was treated with2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution washeated to reflux for 14 h. After cooling to ambient temperature, thesolution was poured into water (100 mL), and solid sodium bicarbonatewas added until CO₂ evolution ceased. The mixture was extracted withEtOAc (2×100 mL), and the extracts were washed with saturated brine,combined, dried over MgSO₄, filtered and concentrated. The residualmaterial was separated by silica gel chromatography (EtOAc/hexanes, 1/4)to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, asa yellow solid (232 mg, 51%).

Example 1U Preparation ofN-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)acetamide (compound 25)

Step A: Sodium hydride (42 mg, 1.05 mmol, 60% w/w suspension in mineraloil) was washed with hexane and taken up in dimethylsulfoxide (1 mL). Asolution of 2-amino-6-nitro-1H-indole-3-carbonitrile, prepared inprocedure 1T) in dimethylsulfoxide (1 mL) was added by syringe, and theresulting mixture was stirred for 20 min. Then, iodoethane (77 μL, 0.96mmol) was added by syringe, and the mixture was stirred for 14 h. Thereaction was then poured into EtOAc (50 mL), and this solution waswashed with water (3×50 mL) and saturated brine (40 mL). The aqueousphases were back-extracted with EtOAc, and the organic extracts werecombined, dried over Na₂SO₄, filtered and evaporated. The residualmaterial was separated by column chromatography over silica gel(EtOAc/hexanes, 1/1) to afford first a small amount of a dialkylatedanalog, then the desired compound,2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (114 mg, 52%), andfinally unreacted starting material. The desired product was isolated asan orange powder.

Step B: Sodium hydride (44 mg, 1.10 mmol, 60% w/w in mineral oil) waswashed with hexanes and suspended in 1,4-dioxane (3 mL). A solution of2-amino-1-ethyl-6-nitro-1H-indole-3-carbonitrile (120 mg, 0.521 mmol),prepared in step B, above, in dioxane (2 mL) was added, and theresulting mixture was allowed to stir for 30 min. Then, acetyl chloride(45 μL, 0.63 mmol) was added by syringe, and the solution was stirredfor an additional 12 h. The reaction was partitioned between water andEtOAc (20 mL each), and the organic phase was washed with brine. Theaqueous phases were back-extracted in sequence with ethyl acetate, andthe organic extracts were combined, dried over MgSO₄, filtered andevaporated. The resulting solid was triturated with Et₂O, collected byfiltration and dried under vacuum to affordN-(3-cyano-1-ethyl-6-nitro-1H-indol-2-yl)-acetamide (100 mg, 71%),compound 25, as an off-white powder.

Using this procedure and substituting the appropriate acid chlorides orchloroformates gave the following compounds: Compounds 23, 26, 35, 36,203, 204, 214, 215, 216.

Example 1V Preparation of N-ethyl-3-phenyl-5-nitroindole (compound 41)

Step A: To a solution of 5-nitroindole (5.00 g, 30.8 mmol) in pyridine(200 mL) at −4° C. was added a solution of pyridinium bromide perbromide(10.99 g, 34.3 mmol) in pyridine (200 mL) dropwise under nitrogen withstirring. After complete addition, the reaction mixture was stirred for5 min at 0° C. The reaction mixture was diluted in 0° C. water (200 mL)and extracted with 200 mL of Et₂O. The organic layer was washed with 6 MHCl (300 mL), 5% NaHCO₃ (300 mL), and brine (300 mL). The organic phasewas dried over MgSO₄ and solvent was removed to give3-bromo-5-nitroindole as a yellow powder, 80% pure with 20%5-nitroindole (6.80 g, 74% yield).

Step B: A solution of 3-bromo-5-nitroindole from above (625 mg, 2.1mmol), phenylboronic acid (381 mg, 3.13 mmol), triphenylphosphine (109.3mg, 0.417 mmol) in dimethoxyethane (4.16 mL) was degassed. To thismixture 2N sodium carbonate (6.25 mL) was added, and reaction mixturewas degassed again. To the reaction was added palladium (II) acetate(23.4 mg, 0.104 mmol), and the reaction was refluxed under dry nitrogenwith stirring for 8 hours. The reaction mixture was then diluted with 1M HCl (100 mL), and extracted with ethyl acetate (100 mL). The organicphase was washed with water (100 mL), and brine (100 mL). The organicphase was dried over MgSO₄ and concentrated in vacuo. The crude productwas purified by chromatography over silica gel (EtOAc/hexanes, 10/90) toafford 3-phenyl-5-nitroindole as an orange powder (45 mg, 9% yield).

Step C: To a mixture of 60% NaH in mineral oil (8.7 mg, 0.630 mmol) andDMF (1.0 mL) was added dropwise a solution of 3-phenyl-5-nitroindole(40.0 mg, 2.1 mmol) in DMF (0.75 mL). The reaction mixture was stirredfor 20 min at 0° C. under N₂. Ethyl iodide (14.8 μL, 0.185 mmol) wasadded dropwise and the reaction mixture was stirred for an additional 3hours. The reaction mixture was diluted with water (250 mL), andextracted with EtOAc (30 mL). The organic phase was washed with water(250 mL) and was then dried over MgSO₄ and the solvent was removed invacuo. The desired N-ethyl-3-phenyl-5-nitroindole was obtained as ayellow powder (40.0 mg, 89.5% yield).

In similar fashion the following compound was prepared: Compound 40

Example 1W Preparation of[3-Cyano-1-(4-methoxyphenyl)-1H-indol-6-yl]-carbamic acid propyl ester(compound 97)

6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol),was suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol)was added, and this mixture was stirred at room temperature overnight.The addition of triethylamine (300 μL), followed by another hour ofstirring at room temperature, completed the reaction. This reactionmixture was loaded directly onto a silica column, and was eluted withCH₂Cl₂. Another silica column (3/2, ether/hexanes) was needed to fullypurify the product,[3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester(19 mg, 45%), as a white solid.

Example 1X Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide(compound 130)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50mg, 0.16 mmol), prepared as described by the method of Example 1H, wasdissolved in pyridine (550 μL) at room temperature. Methanesulfonylchloride (17 μL, 0.21 mmol) was added dropwise. This was stirredovernight at room temperature. The reaction mixture was then diluted inethyl acetate and was washed with aqueous HCl, followed by brine. Theorganic layer was dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yieldedN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-methanesulfonamide(58 mg, 92%) as an off-white solid.

The following compounds were made using the procedure shown above, bysubstituting the appropriate aminophenylethynyl indoles and sulfonylchlorides: Compounds 131, 132, 208, 209, and 210.

Example 1Y Preparation ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamide(compound 129)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in Example 1Ga, step B in THF (3 mL)was cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol)and methanesulfonylchloride (0.02 mL, 0.29 mmol) at stirred, warming toroom temperature overnight. The reaction mixture was then diluted withH₂O and extracted with ethyl acetate (3×). The organic phase was washedwith H₂O and saturated NaCl, dried and concentrated and purified byflash chromatography using EtOAc/hexanes (30-50%) to afford 60 mg (68%)ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-methanesulfonamideas a tan solid.

Using essentially the same procedure as above and substituting theappropriate aminophenylindole and sulfonyl chloride or carrying out thereaction in pyridine as both base and solvent gave the followingcompounds: 83, 85, 86, 87, 88, 243, 251, 252, 272, 273, 287, 289, 365,366, 367, 368, 369, 370, 371, 394, 439, 440, 448, 449, 451, 452, 477,487, 488, 495, 505, 510, 548, 549, 550, 551, 552, 562, 563, 598, 599,601, 602, 608, 609, 610, 615, 616, 617, 621, 622, 623, 629, 630, 631,639, 655, 657, 658, 662, 669, 670, 671, 674, 675, 701, 702, 703, 706,707, 708, 709, 710, 711, 713, 715, 720, 789, 790, 791, 850, 851.

Example 1Za Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide(compound 138)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (95mg, 0.29 mmol), prepared as described in Example 1H, was dissolved inTHF (1.4 mL). Triethylamine (84 μL, 0.6 mmol) was added, followed bydropwise addition of acetyl chloride (44 μL, 0.5 mmol). This was stirredat room temperature for 1 h. The reaction mixture was partitionedbetween H₂O and EtOAc. The organic layer was dried and concentrated.Purification by silica chromatography (9/1, CH₂Cl₂/EtOAc) yieldedN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-acetamide(103 mg, 96%) as a yellow solid.

The following compounds were prepared by the procedure shown above,substituting the appropriate aminophenylethynyl indoles and acidchlorides: Compounds 82, 139, 152, 153, 162, 163, 165, 167, 205, 206,207, 211, 212, 213, 219, 224, 225, 228.

Example 1Zb Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide(compound 241)

Acetic anhydride (2.5 mL) and 98% formic acid (1.0 mL) were heated at65° C. for 1 hour. This was cooled to 0° C.2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as in example 1H, was taken up in THF (1.2 mL)and added to the formic acetic anhydride mixture. This was stirred at 0°C. for 30 minutes. The reaction mixture was then partitioned between H₂Oand EtOAc. The EtOAc layer was washed with saturated NaHCO₃, followed bysaturated brine. The organic layer was dried and concentrated.Purification by silica gel chromatography (4/1, CH₂Cl₂/EtOAc) yielded ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-formamide(105 mg, 96%) as a yellow solid.

The following compound was prepared similarly as described above:Compound 218.

Example 1AA Preparation ofN-[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-acetamide(compound 128)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in example 1Ga, step B in THF (3 mL)was cooled to 0° C. and treated with triethylamine (0.04 mL, 0.31 mmol)and acetyl chloride (0.02 mL, 0.29 mmol) and stirred, warming to roomtemperature overnight. The reaction mixture was then diluted with H₂Oand extracted with ethyl acetate (3×). The organic phase was washed withH₂O and saturated NaCl, dried and concentrated and purified by flashchromatography using EtOAc/hexanes (30-50%) to afford 57 mg (71%) ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]acetamide as a tansolid.

Using essentially the same procedure as above and substitutingappropriate aminophenyl indoles and the acid chlorides, the followingcompounds were prepared: Compounds 81, 242, 244, 324, 325, 326, 327,328, 329, 330, 383, 420, 421, 422, 423, 424, 425, 544, 558, 559, 560,561, 565, 566 567, 644, 645, 646, 755, 756, 757, 759, 760, 761, 762,763, 764, 765, 766, 798, 799, 801, 802, 803, 804, 854, 855, 856, 857,858, 859.

Example 1AB Preparation of1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]-3-ethylurea (compound 220)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, was dissolved inpyridine (670 μL). Ethyl isocyanate (62 μL, 0.75 mmol) was added. Thereaction mixture was then heated at 100° C. for 2 h. The mixture wasthen diluted in EtOAc, and was washed with aqueous HCl, followed bybrine. The organic layer was dried and concentrated. Purification bysilica chromatography (4/1, CH₂Cl₂/EtOAc), followed by trituration withhexanes/acetone (1/1), yielded1-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-3-ethylurea (44 mg, 36%) as a white solid.

Example 1AC Preparation of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (compound 156)

2-(4-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, was suspended intoluene (600 μL). 2-Chloroethyl isocyanate (32 μL, 0.37 mmol) was added,and the mixture was heated at 100° C. for 5 h. The reaction mixture wasthen cooled, diluted in acetone, and absorbed onto silica. Purificationby column chromatography (5-10% EtOAc in CH₂Cl₂) yielded1-(2-chloro-ethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (73 mg, 54%) as a yellow solid.

The following compounds were prepared using the procedure above:Compound 221.

Example 1AD Preparation of Ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide(compound 157)

N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)phenyl]ethanesulfonamide (70 mg, 0.17 mmol), prepared as in example 1X, wascombined with K₂CO₃ (49 mg, 0.35 mmol), and DMF (1.0 mL). Iodomethane(16 μL, 0.26 mmol) was added, and the mixture was stirred at roomtemperature for 1 hour. The reaction mixture was then diluted in EtOAc,and was washed with H₂O and then brine. The organic layer was dried andconcentrated. Purification by silica chromatography (95/5, CH₂Cl₂/EtOAc)yielded a light tan solid. Trituration gave ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]methyl amide(61 mg, 85%) as an orange-white solid.

The following compounds were prepared using the procedure above,substituting the appropriate sulfonamide: Compound 182, 652, 840.

Example 1AE Preparation of1-ethyl-5-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile(compound 245)

Step A: Methyl 4-(3-cyano-1-ethyl-5-methoxy-1H-indol-2-yl)-benzoate (350mg, 1.05 mmol), prepared as described in Example 1Ga step B, wascombined with NaOH (40 mg, 1 mmol), H₂O (0.8 mL), and THF (3.4 mL) andwas heated at 80° C. for 1 hour. The reaction mixture was diluted in H₂Oand was then ether-washed. The aqueous layer was acidified with aqueousHCl, and was extracted into EtOAc. The organic layer was dried andconcentrated to yield4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (311 mg, 92%)as a pure white solid.

Step B: 4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-benzoic acid (50 mg,0.16 mmol) was suspended in CH₂Cl₂ (2.2 mL) and catalytic DMF (2 μL).Oxalyl chloride (22 μL, 0.25 mmol) was added. The reaction mixture wasstirred at room temperature for 1 hour, at which time full dissolutionoccurred. This reaction mixture was pipetted dropwise into a vigorouslystirring solution of morpholine (1.0 mL) in CH₂Cl₂ (5 ml). Afteraddition was complete, the reaction mixture was washed with aqueous HClsolution. The organic layer was dried and concentrated. Purification bysilica column (1:1 CH₂Cl₂/EtOAc) yielded1-ethyl-6-methoxy-2-[4-(morpholine-4-carbonyl)-phenyl]-1H-indole-3-carbonitrile(56 mg, 90%) as a white solid.

The following compounds were prepared similarly as described above:Compounds 113, 114, 246, 270, 271 290, 291, 292, 323, 377, 378, 379,380, 381, 382, 384, 385, 386, 387, 388, 389, 390, 391, 392, 432, 433,564, 568, 569, 570, 571, 572, 573, 647, 648, 853, 860, 861, 862.

Example 1AF Preparation of cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl] amide(compound 194)

Cyclopropanecarboxylic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-amide (60mg, 0.16 mmol), prepared as described in example 1Za, was stirred inBBr₃ (800 μL, 1M in CH₂Cl₂, 0.8 mmol) at room temperature for 1 hour.The reaction mixture was quenched with H₂O, and was extracted withCH₂Cl₂. The organic layer was dried and concentrated. Purification bysilica chromatography (EtOAC) gave impure product. These crude productwas triturated with 1/1 hexanes/acetone to yield cyclopropanecarboxylicacid [4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-ylethynyl)-phenyl]-amide(32 mg, 54%) as an off-white solid.

The following compounds were prepared using the procedure above,substituting the appropriate sulfonamides (from example 1X) or amides(from Example 1Z): Compounds 164, 168, 183, 193, 195.

Example 1AG Preparation of1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile(compound 166)

1-(2-Chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]urea (55 mg, 0.13 mmol), prepared as in Example 1AC, was combined withK₂CO₃ (50 mg, 0.36 mmol) and DMF (550 μL). This mixture was stirred atroom temperature for 3 hours. The reaction mixture was diluted in EtOAc,and was washed with H₂O, and then with brine. The organic layer wasdried and concentrated. Purification by silica chromatography (10-50%,EtOAc/CH₂Cl₂) yielded1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenylethynyl]-1H-indole-3-carbonitrile(47 mg, 94%) as a white solid.

The following compounds were prepared using the above procedure,substituting the appropriate urea: Compound 222.

Example 1AH Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinicamide (compound 227)

2-(3-Aminophenylethynyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100mg, 0.32 mmol), prepared as described in Example 1H, was dissolved inpyridine (300 μL) at 0° C. Dimethylphosphinic chloride (60 mg, 0.53mmol) in THF (300 μL) was added. The reaction was stirred at roomtemperature for 2 hours. The reaction mixture was diluted in EtOAc, andwas washed with aqueous HCl followed by brine. The organic layer wasdried and concentrated. Purification by silica chromatography (acetone)yieldedN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-dimethylphosphinicamide (65 mg, 52%), compound 227, as a pure white solid. The silicacolumn was then flushed with 9/1 CH₂Cl₂/MeOH to yield 9 mg ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-ylethynyl)-phenyl]-bis-(dimethylphosphinic)amide as a by-product.

Example 1AI Preparation of1-ethyl-6-methoxy-3-[5-(4-methoxyphenyl)-isoxazol-3-yl]-1H-indole(compound 116)

Step A: A mixture of 1-ethyl-6-methoxy-1H-indole-3-carbaldehyde oxime(0.20 g, 0.92 mmol), prepared from the aldehyde precursor in example 1R,in dichloroethane (3 mL) was treated with N-chlorosuccinimide (0.12 g,0.92 mmol) and pyridine (0.04 mL, 0.46 mmol) and stirred at roomtemperature for 1 h. The reaction mixture was then poured into H₂O andacidified with 1N HCl until the pH was 2. The mixture was extracted withEtOAc and the organic phases were washed with H₂O and saturated NaCl anddried and concentrated to a mixture of chlorooximes, which were used inthe next step without further purification.

Step B: The mixture of chlorooximes prepared above was dissolved inCH₂Cl₂ (5 mL) and to this was added 4-methoxyphenylacetylene (0.24 g,1.84 mmol) and triethylamine (0.25 mL, 1.84 mmol) at 0° C. and thereaction was then stirred overnight warming to room temperature. Thereaction was then diluted with H₂O and extracted with EtOAc (3×). Theorganic phases were washed with H₂O and saturated NaCl and dried andconcentrated. Chromatography over silica gel (EtOAc/hexanes, 10-20%)gave 76 mg (24%) of1-ethyl-6-methoxy-3-[5-(4-methoxy-phenyl)-isoxazol-3-yl]-1H-indole as atan solid.

Example 1AJ Preparation of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (compound 121)

A biphasic mixture of2-(4-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (70 mg,0.24 mmol), prepared as described in example 1Ga step B, and ethylchloroformate (0.03 mL, 0.29 mmol) in EtOAc (3 mL) and saturated NaHCO₃(3 mL) was prepared at 0° C. and then allowed to warm to roomtemperature and stirred for 24 h. The reaction was then diluted with H₂Oand extracted with EtOAc (2×). The organic phases were washed with H₂Oand saturated NaCl and then dried and concentrated. Flash chromatography(EtOAc/hexanes 20-40%) gave 48 mg (55%) of[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester as an off-white solid.

The following compound was prepared in similar fashion: Compound 122,293, 294, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307,308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 372,434, 435, 450, 453, 454, 455, 457, 485, 486, 489, 490, 500, 501, 502,503, 506, 507, 508, 509, 545, 546, 547, 553, 554, 555, 556, 557, 581,582, 583, 584, 585, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594,595, 596, 597, 603, 604, 605, 606, 607, 618, 619, 624, 625, 637, 640,641, 664, 665, 676, 677, 721, 722, 723, 734, 735, 736, 737, 738, 739,744, 745, 746, 747, 787, 788, 792, 793, 794, 795, 796, 797, 819, 822,823, 824, 825, 826, 849.

Example 1AK Preparation of1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile (compound 141)

A tube was charged with a mixture of5-bromo-1-ethyl-1H-indole-3-carbonitrile (100 mg, 0.40 mmol),thiophene-3-boronic acid (72 mg, 0.56 mmol), PdCl₂(PPh₃)₂ (11 mg, 0.016mmol) and CsF (152 mg, 1 mmol) and then alternately evacuated and filledwith nitrogen (3×) and diluted with dimethoxyethane (3 mL) and thenheated to 90° C. for 19 h. After cooling, the crude reaction mixture wasdiluted with saturated NaHCO₃ and extracted with EtOAc (2×). Thecombined organic phases were washed with saturated NaCl and dried andconcentrated. Flash chromatography over silica gel (CH₂Cl₂/hexanes,40/60) gave 25 mg (25%) of1-ethyl-5-thiophen-3-yl-1H-indole-3-carbonitrile as a white solid.

The following compounds were prepared in similar fashion: Compounds 140and 142.

Example 1AL Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methylmethanesulfonamide (compound 180)

A solution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) wastreated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for10 min. Iodomethane (0.03 mL, 0.53 mmol) was added, and the mixture wasstirred at room temperature for 18 h. The reaction mixture was thendiluted with H₂O, and extracted with EtOAc (2×). The organic phases werewashed with H₂O and saturated NaCl and then dried and concentrated.Purification by flash chromatography over silica gel (EtOAc/CH₂Cl₂,0-1%) gave 60 mg (45%) ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methylmethanesulfonamide as a white solid.

In similar fashion the following compounds were prepared: Compounds 181,642, 643, 672, 673, 816, 852.

Example 1AM Preparation ofN-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-methanesulfonamide(compound 189)

A solution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(85 mg, 0.23 mmol) in CH₂Cl₂ (2 mL) was cooled to −5° C. A solution ofboron tribromide (1.15 mL, 1.15 mmol, 1M solution in CH₂Cl₂) was addedand the reaction mixture was allowed to warm to 110° C. over 4 h. Thereaction mixture was poured into H₂O and extracted with EtOAc (3×). Thecombined organic phases were washed with H₂O and saturated NaCl anddried and concentrated. Chromatography over silica gel (EtOAc/CH₂Cl₂,5-10%) gave 18 mg (22%) ofN-[4-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]methanesulfonamide as a tan solid.

The following compounds were made similarly: Compounds 190, 191, 192.

Example 1AN Preparation of methyl3-[5-(3-cyano-6-methoxy-1H-indol-2-yl)-[1,2,4]oxadiazol-3-yl]benzoate(compound 226)

Step A: To a mixture of 6-methoxy-1H-indole-3-carbonitrile (5.88 g, 40mmol), prepared as described in the previous examples, and (Boc)₂O (9.59g, 44.0 mmol) in DCM (50 mL) was added DMAP (0.10 g, 0.8 mmol). Themixture was stirred at room temperature for 48 h, then treated withwater (30 mL) and dried over anhydrous Na₂SO₄. The crude product waschromatographed over silica gel (hexanes/EtOAc, 7/1) to furnish thedesired intermediate, 3-cyano-6-methoxyindole-1-carboxylic acidtert-butyl ester (8.48 g, 86%).

Step B: The above intermediate (2.72 g, 10.0 mmol) was dissolved inanhydrous THF (20 mL), and cooled at −78° C., followed by the additionof LDA (1.5 M monoTHF in cyclohexane, 10.0 mL, 15 mmol). After stirringfor 45 min, CO₂ gas was introduced for 2 h. The mixture was then broughtto room temperature and the solvent was removed in vacuo, and theresidue was treated with water and acidified to pH=2 with 6 N HCl. Theprecipitate was collected and washed with water and dried to provide theacid intermediate, 3-cyano-6-methoxy-indole-1,2-dicarboxylic acid1-tert-butyl ester (2.40 g, 73%).

Step C: To a solution of 3-cyano-6-methoxyindole-1,2-dicarboxylic acid1-tert-butyl ester (474 mg, 1.5 mmol) prepared above, and HOBt (200 mg,1.5 mmol) in DCE/DMF (10 mL/1 mL), was added DCC (310 mg, 1.5 mmol),followed by 3-(N-hydroxycarbamimidoyl)benzoic acid methyl ester (291 mg,1.5 mmol). The mixture was stirred at room temperature for 2 h andfiltered. The filtrate was collected and the solvent was replaced withchlorobenzene, followed by the heating at 150° C. for 48 h. Aftercooling to room temperature, the solvent was removed in vacuo and theresidue was chromatographed (silica gel, CH₂Cl₂/EtOAc, 8/2) to furnishthe intermediate,3-cyano-6-methoxy-2-[3-(3-methoxycarbonylphenyl)-[1,2,4]oxadiazol-5-yl]-indole-1-carboxylicacid tert-butyl ester, which was treated with 50% TFA in DCM (10.0 mL)at room temperature for 1 h. After removal of the volatiles in vacuo,the residue was suspended in water and neutralized with K₂CO₃ to providethe desired product, methyl3-[5-(3-cyano-6-methoxy-1H-indol-2-yl-)[1,2,4]oxadiazol-3-yl]benzoate,compound 226 (350 mg, 62%).

Example 1AO Preparation of1-ethyl-2-(4-methanesulfonylphenyl)-6-methoxy-1H-indole-3-carbonitrile(compound 265)

A solution of1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile(0.12 g, 0.37 mmol) in CH₂Cl₂ (5 mL) was treated with m-chloroperbenzoicacid (Aldrich, <77%, 0.26 g,) in one portion and the reaction wasstirred for 10 h at room temperature. The reaction was then diluted withH₂O and saturated NaHCO₃ and extracted twice with EtOAc. The organicphases were washed with NaHCO₃ (2×) and saturated NaCl and dried andconcentrated to a dark semi-solid. The crude product was purified byflash chromatography (EtOAc/CH2Cl2, 0-3%) through a 5 gram silicacartridge topped with 1 gram of basic alumina to give 72 mg (55%) of1-ethyl-6-methoxy-2-(4-methylsulfanylphenyl)-1H-indole-3-carbonitrile asan off-white solid.

Example 1AP Preparation ofN-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide (compound 478)

A solution ofN-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol),NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol)in CH₃CN (2 mL) was heated in a sealed tube at 100° C. for 25 h. Thereaction mixture was cooled to room temperature, diluted with H₂O andextracted with EtOAc (3×). The combined organic phases were washed withsaturated NaCl, dried and concentrated. The crude solid was trituratedwith EtOAc and filtered to give 41 mg (41%) ofN-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide as a tan solid.

The following compounds were made similarly: Compounds 479, 480, 481,482, 496, 497 and 498.

Example 1AQ Preparation of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide (compound653)

Step A: A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, preparedby example 1Ga step B, (0.82 mg, 2.82 mmol), in pyridine (10 mL) wastreated dropwise with chloroethyl sulfonylchloride (0.38 mL, 3.66 mmol)at room temperature. After stirring for 4 h, the reaction mixture wasquenched with ice-water and enough 6N HCl was added until the pH waslowered to 2. The suspension was extracted with hot EtOAc (3×). Theorganic phases were then washed sequentially with 1N HCl, H₂O andsaturated NaCl and dried and concentrated to give ethenesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide as a paleorange solid which was used directly in the next step without furtherpurification.

Step B: A suspension of ethenesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, preparedabove, (70 mg, 0.18 mmol), morpholine (0.05 mL, 0.55 mmol) in CH₃CN (1.5mL) was heated at reflux for 1.5 h. After cooling to room temperature,the reaction was concentrated and the residue was purified by flashchromatography (acetone/EtOAc, 2/98) over silica gel to afford 89 mg(100%) of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide as a tanfoam.

The following compound was made similarly: Compound 654.

Example 1AR Preparation of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide(compound 668)

A solution of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, prepared inexample 1AQ (60 mg, 0.13 mmol) in DMF (3 mL) was treated with K₂CO₃ (35mg, 0.26 mmol) and methyl iodide (0.02 mL, 0.26 mmol). After stirring atroom temperature for 1.5 h, the reaction mixture was diluted with H₂Oand extracted with EtOAc (2×). The organic phases were then washed withH₂O (3×) and saturated NaCl, and then dried and concentrated to afford aresidue. Flash chromatography over silica gel (acetone/EtOAc, 0-2%) gave31 mg (50%) of 2-morpholin-4-yl-ethanesulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methyl amide as anoff white solid.

The following compounds were made similarly: Compounds 684, 685, 686,687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698.

Example 1AS Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(compound 84)

Step A: A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile, preparedby example 1Ga step B, (2.78 g, 9.55 mmol) in pyridine (40 mL) wastreated dropwise with 3-chloropropanesulfonyl chloride (1.45 mL, 11.9mmol) and the reaction was stirred for 4 h at room temperature. Thereaction was diluted with water and enough 6N HCl to lower the pH to 2.The reaction mixture was extracted with EtOAc (3×) and the combinedorganic layers were washed sequentially with 1N HCl, water and saturatedNaCl and then dried and concentrated to give 3.9 g (95%), of3-chloropropane-1-sulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide as a brownfoam which was used directly in the next step.

Step B: A solution of 3-chloropropane-1-sulfonic acid[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl] amide, preparedabove (3.65 g, 2.33 mmol) in DMF (100 mL) was treated with K₂CO₃ andheated at 70° C. for 2 h. After cooling to room temperature, thereaction mixture was diluted with H₂O and extracted 3× with hot EtOAc.The hot organic layers were washed with warm H₂O (3×) and saturated NaCland dried and concentrated to a solid. Trituration (CH₂Cl₂/hexanes) gave2.27 g (68%) of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrileas a light brown solid.

The following compounds were made in similar fashion: Compound 649, 775.

Example 1AT Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(compound 666)

Step A: Following the procedure in example 1B step A,2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrilewas treated with 1M BBr₃ solution in CH₂Cl₂ at −15° C. for 1.5 h andthen poured into ice-water and filtered and dried to afford2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrilein nearly quantitative yield.

Step B: Following the procedure in example 1B step B,2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile,K₂CO₃, 2-iodopropane and methyl ethyl ketone were heated at reflux togive, after flash chromatography (EtOAc/CH₂Cl₂, 0-2%), 61% of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-isopropoxy-1H-indole-3-carbonitrileas an off-white solid.

The following compounds were made similarly: Compounds 667, 699

Example 1AU Preparation of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrile(compound 729)

A mixture of2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)phenyl]-1-ethyl-6-hydroxy-1H-indole-3-carbonitrile,prepared in example 1AT above (70 mg, 0.25 mmol), K₂CO₃ (75 mg, 0.51mmol), sodium iodide (27 mg, 0.18 mmol), 4-(2-chloroethyl) morpholinehydrochloride (42 mg, 0.25 mmol) in methyl ethyl ketone (3 mL) washeated in a sealed tube at 100° C. After 13 hours, DMF (3 mL) was addedand the reaction was heated for an additional 6 h. After this time, anadditional 42 mg of 4-(2-chloroethyl) morpholine hydrochloride and 135mg of K₂CO₃ was added and the reaction was heated for an additional 6 hto complete the reaction. The reaction mixture was cooled to roomtemperature, diluted with water, and extracted with EtOAc (3×). Thecombined organic phases were washed with water (2×) and saturated NaCland dried and concentrated. Pure2-[4-(1,1-dioxo-1λ⁶-isothiazolidin-2-yl)-phenyl]-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indole-3-carbonitrilewas obtained by flash chromatography (MeOH/CH₂Cl₂, 0-6%) to give 29 mg(34%) of a tan solid.

The following compounds were made similarly: Compounds 728 and 730.

Example 1AV Preparation of2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(compound 779)

Step A: A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (585 mg,1.92 mmol) in 10 mL of 1,4-dioxane was treated with ethylisocyanatoacetate (0.25 mL, 2.12 mmol), and the resulting solution washeated to reflux overnight. The solution was allowed to cool, and thesolvent was removed by rotary evaporation. The residual material wastriturated with ether, and the resulting precipitate was collected byfiltration and dried under vacuum to afford compound 773 (587 mg, 1.35mmol, 70%).

A similar procedure was used to prepare methyl2-{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-3-phenyl-propionate(compound 777)

Step B: A solution of ethyl{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}-acetate(compound 773, 101 mg, 0.232 mmol) in THF (10 mL) was treated with asolution of potassium tert-butoxide in tert-butanol (0.30 mL, 1.0 M,0.30 mmol), and the resulting mixture was allowed to stir overnight. Thereaction mixture was partitioned between water and ethyl acetate (50 mLeach), and the organic phase was washed with saturated brine. Theaqueous phases were extracted with more ethyl acetate, and the extractswere combined, dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material was separated by column chromatography(eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile,compound 779, which was purified further by trituration with ether,collection by filtration and drying under high vacuum (76 mg, 0.196mmol, 84%).

Example 1AW Preparation of2-[4-(2,4-dioxo-imidazolidin-1-yl)phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile(compound 776)

A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (319 mg,1.04 mmol) in 1,4-dioxane (3 mL) was treated with chloroacetylisocyanate (0.10 mL, 1.17 mmol), and the resulting solution was warmedto 60° C. overnight. The solution was cooled, and DBU (0.20 mL, 1.31mmol) was added. This mixture was stirred at ambient temperatureovernight, and then was partitioned between water and ethyl acetate (50mL each). The organic layer was washed with saturated brine, and thendried over anhydrous magnesium sulfate, filtered and evaporated. Theresidual material was triturated with ether, and the resulting solid wascollected by filtration and dried under high vacuum to afford the titleproduct (319 mg, 0.821 mmol, 79%).

Example 1AX Preparation ofN,N-Dimethyl-2-[4-(3,4-dimethyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-6-ethoxy-1-ethyl-1H-indole-3-carboxamide(compound 780) andN,N-Dimethyl-6-ethoxy-1-ethyl-2-[4-(3-methyl-2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(compound 781)

Step A. A solution of ethyl{3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido} acetate(compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A,in acetone (5 mL) was treated with HCl (3 mL, 6 N), and the resultingsolution was heated to reflux overnight. The reaction mixture wascooled, and the resulting precipitate was collected by filtration,washed with ether and dried under high vacuum to afford the product,6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(264 mg, 0.650 mmol, 87%).

Step B. Sodium hydride dispersion in mineral oil (75 mg) was washed witha small portion of hexane, and the hexane layer was decanted off. Asolution of6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide(190 mg, 0.468 mmol) in dimethylformamide (2 mL) was added, and themixture was stirred for 1 hour. Then, methyl iodide (0.10 mL, 1.61 mmol)was added by syringe. The resulting mixture was allowed to stir atambient temperature overnight and then was poured into 50 mL of ethylacetate. The organic phase was washed with water (3×50 mL) and saturatedbrine (20 mL), then dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material was separated by column chromatogaphy(1/1 ethyl acetate/hexane, eluting on silica gel 60) to afford the titleproducts, compounds 780 and 781.

Example 1AY Preparation ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)-methanesulfonamide(compound 828)

Step A: Sodium hydride dispersion in mineral oil (108 mg) was washedwith a small portion of hexane, and the hexane layer was decanted off. Asolution ofN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(compound 129, 500 mg, 1.35 mmol) in DMF (5 mL) was slowly added. Aftergas evolution was complete, 2-bromoethyl acetate (0.30 mL, 2.64 mmol)and sodium iodide (20 mg) were added. The mixture was stirred at ambienttemperature overnight, and then was poured into 50 mL of ethyl acetate.This was washed with water (3×50 mL) and saturated brine (20 mL), thendried over anhydrous magnesium sulfate, filtered and evaporated. Theresidual material was separated by column chromatogaphy (1/1 ethylacetate/hexane, eluting on silica gel 60) to afford compound 815 (364mg, 0.799 mmol, 59%).

Step B: A mixture ofN-(2-acetoxyethyl)-N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide(compound 815, 164 mg, 0.360 mmol) and lithium hydroxide hydrate (45 mg,1.07 mmol) in 5 mL THF/1 mL water was warmed to 60° C. overnight. Themixture was cooled and poured into ethyl acetate (50 mL). This waswashed with water (50 mL) and brine (20 mL), dried over anhydrousmagnesium sulfate, filtered and evaporated to afford a solid. The solidwas triturated with ether, collected by filtration and dried under highvacuum to affordN-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-(2-hydroxyethyl)methanesulfonamide, compound 828 (137 mg, 0.331 mmol, 92%).

Example 1AZ Preparation of1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile(compound 248)

1-Ethyl-2-(4-hydroxy-phenyl)-6-methoxy-1H-indole-3-carbonitrile (40 mg,0.14 mmol), prepared as in example 1Ga step B, was combined with K₂CO₃(77 mg, 0.56 mmol), bromoethyl methyl ether (26 μL, 0.28 mmol), and DMF(450 μL). This was stirred at room temperature for 1 hour, and then at75° C. for 3 hours. The reaction mixture was then partitioned betweenH₂O and EtOAc. The organic layer was dried and concentrated.Purification by silica gel chromatography (CH₂Cl₂, 0-5% EtOAc) to yield1-ethyl-6-methoxy-2-[4-(2-methoxyethoxy)-phenyl]-1H-indole-3-carbonitrile(44 mg, 90%) as a white solid.

The following compound was prepared similarly as above: Compound 249.

Example 1BA Preparation of1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile(compound 261)

Step A:1-Ethyl-6-methoxy-2-[4-(2-hydroxyethoxy)-phenyl]-1H-indole-3-carbonitrile(450 mg, 1.34 mmol), prepared as in example 1AZ, was combined with PPh₃(878 mg, 3.35 mmol) in CH₂Cl₂ (32 mL) at 0° C. N-bromosuccinimide (600mg, 3.37 mmol) was added in one portion. The reaction mixture wasstirred at room temperature for 30 minutes. The reaction mixture waswashed with aqueous NaHCO₃. The organic layer was dried andconcentrated, and purified by silica gel chromatography (CH₂Cl₂) toyield2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(506 mg, 95%), compound 253 as a white solid.

Step B:2-[4-(2-bromoethoxy)-phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(40 mg, 0.1 mmol), prepared as in step A above, was combined withmorpholine (50 μL, 0.58 mmol) and acetonitrile (1.0 mL). This was heatedat 85° C. for 2 h. The reaction mixture was then partitioned betweenCH₂Cl₂ and H₂O. The organic layer was dried and concentrated.Purification by silica gel chromatography (6/4, acetone/hexanes) yielded1-ethyl-6-methoxy-2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-1H-indole-3-carbonitrile(39 mg, 96%) as a white solid.

The following compounds were prepared similarly as above, usingdifferent amines: Compounds 262, 263, 264.

Example 1BB Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}methanesulfonamide (compound 268)

Step A:2-[4-(2-Bromoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(258 mg, 0.65 mmol), prepared in example 1BA, step A, was combined withNaN₃ (144 mg, 2.2 mmol), and MeOH (3.2 mL). This was heated overnight at75° C. The reaction mixture was then partitioned between CH₂Cl₂ and H₂O.The organic layer was dried and concentrated. Purification by silica gelchromatography (CH₂Cl₂) yielded2-[4-(2-azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(187 mg, 80%), compound 266 as a white solid.

Step B:2-[4-(2-Azidoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(410 mg, 1.14 mmol), prepared as in step A, above, was suspended in asolution of MeOH (20 mL) and concentrated HCl (500 μL). Pd/C (150 mg,10%) was added, and this mixture was hydrogenated at 30 p.s.i. for 1 h.This was filtered and the filtrate was concentrated. The filtrateresidue was partitioned between EtOAc and 0.5N NaOH. The organic layerwas dried and concentrated. Purification by silica gel chromatography(10-30%, MeOH/CH₂Cl₂) yielded2-[4-(2-aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(298 mg, 78%), compound 267, as a white solid.

Step C:2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared in step B, above, was dissolved in pyridine(300 μL). Methanesulfonyl chloride (8 μL, 0.1 mmol) was added. This wasstirred at room temperature for 45 minutes. More methansulfonyl chloride(4 μL, 0.05 mmol) was added. Stirring continued for another hour. Thereaction mixture was partitioned between EtOAc and aqueous HCl. Theorganic layer was dried and concentrated. Purification by silica gelchromatography (1/1 CH₂Cl₂/EtOAc) yieldedN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}methanesulfonamide, compound 268 (32 mg, 86%) as a white solid.

The following compound was prepared similarly as above: Compound 269.

Example 1BC Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}acetamide (compound 274)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, step B, was dissolved inTHF (400 μL), and Et₃N (24 μL, 0.17 mmol). Acetyl chloride (10 μL, 0.14mmol) was added, and the reaction mixture was stirred at roomtemperature for 2 h. The reaction mixture was partitioned between EtOAcand H₂O. The organic layer was dried and concentrated. Purification bysilica gel chromatography (EtOAc) yieldedN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]ethyl}acetamide (33 mg, 97%) as a white solid.

Example 1BD Preparation of1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}-3-ethyl-urea(Compound 279)

2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, was combined with ethylisocyanate (18 μL, 0.21 mmol) and pyridine (300 μL). This mixture wasstirred at room temperature for 90 minutes, and was then partitionedbetween EtOAc and aqueous HCl. The organic layer was dried andconcentrated. Purification by silica gel chromatography (EtOAc) yielded1-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-ethyl}-3-ethyl-urea(34 mg, 93%) as a white solid.

Example 1BE Preparation ofN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]ethyl}formamide(compound 280)

Acetic anhydride (700 μL) and 98% formic acid (280 μL) were heated at65° C. for 1 h. This was cooled to 0° C.2-[4-(2-Aminoethoxy)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(30 mg, 0.09 mmol), prepared as in example 1BB, was taken up in THF (400μL), and added to the mixed anhydride. This was stirred at 0° C. for 45minutes. The mixture was then portioned between EtOAc and aqueousNaHCO₃. The organic layer was dried and concentrated. Purification bysilica gel chromatography (4/1, CH₂Cl₂/acetone) yieldedN-{2-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenoxy]-ethyl}formamide (28 mg, 86%) as a white solid.

Example 1BF Preparation of1-ethyl-2-{4-[2-(3-hydroxypyrrolidin-1-yl)-2-oxo-ethoxy]phenyl}-6-methoxy-1H-indole-3-carbonitrile(compound 285)

Step A: 1-Ethyl-2-(4-hydroxyphenyl)-6-methoxy-1H-indole-3-carbonitrile(559 mg, 1.91 mmol), was used to prepare[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acidtert-butyl ester (780 mg, 100%) utilizing essentially the same procedureas example 1AZ.

Step B: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-aceticacid tert-butyl ester (745 mg, 1.83 mmol) was stirred in 20% TFA inCH₂Cl₂ at room temperature for 3 hours. This was concentrated and theresidue was partitioned between H₂O and EtOAc. The organic layer wasdried and concentrated. The residue was triturated with CH₂Cl₂ to yield[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (634mg, 99%) as a white solid.

Step C: [4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-aceticacid (40 mg, 0.12 mmol) was suspended in CH₂Cl₂ (1.65 mmol) and DMF (2μL). Oxalyl chloride (17 μL, 0.19 mmol) was added. This was stirred atroom temperature for 30 minutes. The resulting solution was thenpipetted into a stirring solution of S-3-hydroxypyrrolidine (150 μL) andCH₂Cl₂ (3.0 mL). The mixture was washed with aqueous HCl. The organiclayer was dried and concentrated. Purification by silica gelchromatography (3/2 CH₂Cl₂/acetone) yielded1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl}-6-methoxy-1H-indole-3-carbonitrile(40 mg, 79%), compound 285 as a white solid.

Example 1BG Preparation of1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile(Compound 332)

Step A:1-Ethyl-2-(4-hydroxy-3-nitrophenyl)-6-methoxy-1H-indole-3-carbonitrile(369 mg, 1.1 mmol), prepared as in example 1Gd, was combined with EtOAc(20 mL) and Pd/C (150 mg, 10%). This mixture was hydrogenated at 30p.s.i. for 1 h. This was filtered through celite. The filtrate wasconcentrated and triturated with ether to yield2-(3-amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(307 mg, 91%), compound 322, as a white solid.

Step B:2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(100 mg, 0.33 mmol), prepared as in step A, was combined with CDI (83mg, 0.51 mmol), and THF (1.1 mL). This was heated at 65° C. for 1 hour.The reaction mixture was partitioned between EtOAc and aqueous HCl. Theorganic layer was dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yielded1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-5-yl)-1H-indole-3-carbonitrile(89 mg, 81%) as a white solid.

Example 1BH Preparation of1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (compound 334)

Step A: Bromoacetic acid (52 mg, 0.37 mmol) was combined with EDCIhydrochloride (62 mg, 0.4 mmol) and acetonitrile (900 μL) to form ahomogeneous solution.2-(3-Amino-4-hydroxyphenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(100 mg, 0.33 mmol), prepared as in example 1BG, step B, was added tothe solution. A thick paste soon formed. Another 1.1 mL of acetonitrilewas added and the mixture was then stirred at room temperature for 2hours. The reaction mixture was then partitioned between H₂O and EtOAc.The organic layer was dried and concentrated. Purification by silica gelchromatography (4/1, CH₂Cl₂/EtOAc) yielded2-chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxyphenyl]acetamide (82 mg, 60%), compound 333, as a white solid.

Step B:2-Chloro-N-[5-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-2-hydroxy-phenyl]acetamide (57 mg, 0.13 mmol), prepared in step A, was combined withK₂CO₃ (55 mg, 0.4 mmol), and DMF (400 μL). This was heated at 80° C. for1 hour. The reaction mixture was then partitioned between H₂O and EtOAc.The organic layer was dried and concentrated. Purification by silica gelchromatography (9/1, CH₂Cl₂/EtOAc) yielded1-ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(45 mg, 90%) as a white solid.

Example 1BI Preparation of1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile(Compound 340)

Step A: 4-Aminosalicylic acid (4.0 g, 26 mmol) was suspended in H₂SO₄(26 mL, 2.7M) at −5° C. Sodium nitrite (1.8 g, 26.1 mmol) in H₂O (6.5mL) was cooled to ice bath temperature and was added dropwise to theaminosalicylic acid mixture over 5 minutes. The resulting suspension wasstirred at −5° C. for 15 minutes. A solution of KI (6.8 g, 41 mmol) inH₂SO₄ (13 mL, 1M) was added dropwise to the diazonium salt, withconsiderable evolution of N₂. The reaction mixture was heated at 70° C.for 20 minutes. The reaction mixture was then partitioned between H₂Oand EtOAc. The organic layer was dried and concentrated. Purification bysilica gel chromatography (7/3, hexanes/acetone, 1% acetic acid) yielded4-iodosalicylic acid (5.33 g, 85-90% pure).

Step B: Crude 4-Iodosalicylic acid (1.0 g, 3.8 mmol) was dissolved inTHF (28 mL) and Et₃N (1.15 mL, 8.2 mmol). DPPA (1.7 mL, 7.8 mmol) wasadded. This was heated at 70° C. overnight. The reaction mixture wasthen partitioned between H₂O and EtOAc. The organic layer was dried andconcentrated. Purification by silica gel chromatography (9/1,CH₂Cl₂/EtOAc) yielded 472 mg crude intermediate. Trituration with etheryielded 6-iodo-3H-benzooxazol-2-one (369 mg, 37%) as a white solid.

Step C: 6-Iodo-3H-benzooxazol-2-one (118 mg, 0.45 mmol) was used toprepare1-ethyl-6-methoxy-2-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-1H-indole-3-carbonitrile,compound 340 (75 mg, 55%), utilizing essentially the same procedure asin example 1Gd.

Example 1BJ Preparation of1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(compound 339)

1-Ethyl-6-methoxy-2-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile (20 mg, 0.058 mmol), preparedas in example 1BH, was combined with NaH (14 mg, 60% suspension in oil,0.35 mmol). THF (300 μL) was added. This was stirred at room temperaturefor 5 minutes. A solution of methyl iodide (4.4 μL) in THF (100 μL) wasadded. This was stirred at room temperature for 1 hour. The reactionmixture was partitioned between EtOAc and aqueous HCl. The organic layerwas dried and concentrated. Purification by silica gel chromatography(9/1, CH₂Cl₂/EtOAc) yielded1-ethyl-6-methoxy-2-(4-methyl-3-oxo-3,4,-dihydro-2H-benzo[1,4]oxazin-6-yl)-1H-indole-3-carbonitrile(16 mg, 76%) as a white solid.

The following compound was prepared similarly: Compound 341.

Example 1BK Preparation of1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (compound 499)

1-Ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (50 mg, 0.15 mmol),prepared as in example 1Ga, Step A, was suspended in acetic acid (620μL) at 0° C. Nitric acid (4.25M in AcOH) was added. This was stirred atroom temperature for 2 hours. The reaction mixture was then partitionedbetween CH₂Cl₂ and H₂O. The organic layer was washed with aqueousNaHCO₃, and then was dried and concentrated. Purification by silica gelchromatography (6/4, CH₂Cl₂/hexanes), followed by ether trituration,yielded 1-ethyl-2-iodo-6-methoxy-5-nitro-1H-indole-3-carbonitrile (16mg, 29%) as a yellow solid.

Example 1BL Preparation of1′-ethanesulfonyl-1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(compound 753)

Step A: 6-Nitroindoline (3.0 g, 18.3 mmol) was dissolved in THF (45 mL)and Et₃N (3.4 mL, 24.4 mmol) at 0° C. Acetyl chloride (1.5 mL, 21 mmol)was added dropwise. The mixture was stirred at room temperature for 30minutes. The mixture was partitioned between EtOAc and aqueous HCl. Theorganic layer was dried and concentrated to yield1-acetyl-6-nitroindoline (3.8 g, 100%) as a yellow solid.

Step B: 1-Acetyl-6-nitroindoline (3.8 g, 18.3 mmol) was suspended inEtOAc (200 mL). Pd/C (650 mg, 10%) was added, and the mixture washydrogenated at 40-55 p.si.i. for 2 hours. The mixture was then filteredthrough celite. The filtrate was concentrated, and the residue wastriturated with ether to yield 1-acetyl-6-aminoindoline (3.18 g, 99%) asan orange solid.

Step C: 1-Acetyl-6-aminoindoline (1.5 g, 8.5 mmol) was used to prepare1-acetyl-6-iodoindoline (1.06 g, 43%), utilizing essentially the sameprocedure in example 1BI, Step A.

Step D: 1-Acetyl-6-iodoindoline (1.06 g, 3.7 mmol), NaOH (1.16 g, 29mmol), EtOH (8 mL), and H₂O (6 mL) were heated at 90° C. overnight. Thereaction mixture was then partitioned between H₂O and EtOAc. The organiclayer was extracted into aqueous HCl. The aqueous layer was in turnbasified with NaOH, and was extracted with EtOAc. The organic layer wasdried and concentrated. Hexane trituration yielded 6-iodoindoline (577mg, 64%) as a brown solid.

Step E: 1-Iodoindoline (600 mg, 2.45 mmol) was used to prepare1-ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(535 mg, 67%), utilizing essentially the same procedure as in example1Gd, Step B.

Step F:1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(30 mg, 0.095 mmol) was used to prepare1′-Ethanesulfonyl-1-Ethyl-6-methoxy-2′,3′-dihydro-1H,1H′-[2,6′]biindolyl-3-carbonitrile(24 mg, 62%), utilizing the procedure in example 1Y.

The following compounds were prepared similarly as above: Compounds 752and 754.

Example 1BM Preparation of5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(compound 844)

1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile (100 mg,0.3 mmol), prepared by the method of example 1Gc was suspended in1,2-dichloroethane (500 mL) at 0° C. Acetyl chloride (50 μL, 0.69 mmol)was added, followed by AlCl₃ (55 mg, 0.4 mmol) in one portion. This wasstirred at 0° C. for 1 hour, at room temperature for 4 hours, and at 45°C. overnight. The reaction mixture was then partitioned between CH₂Cl₂and H₂O. The organic layer was dried and concentrated. Purification bysilica gel chromatography (195:5 CH₂Cl₂/EtOAc) yielded5-acetyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(33 mg, 29%) as an orange solid.

Example 1BN Preparation of1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(compound 845)

Step A: 1-Ethyl-6-methoxy-2-(4-nitrophenyl)-1H-indole-3-carbonitrile(100 mg, 0.3 mmol), prepared by the method of example 1Gc, was combinedwith 1,3,5-trioxane (64 mg, 0.71 mmol) and acetic acid (2.0 mL). 33% HBrin acetic acid (2.0 mL) was added. This was stirred at room temperaturefor 4 hours. The reaction mixture was then partitioned between CH₂Cl₂and H₂O. The organic layer was washed with aqueous NaHCO₃, and wassubsequently dried and concentrated. The crude material was carriedthrough to the next step.

Step B: Crude6-bromomethyl-1-ethyl-6-methoxy-2-(4-nitro-phenyl)-1H-indole-3-carbonitrile(0.3 mmol) was heated with morpholine (150 μL, 1.75 mmol) and DCE (1.0mL) at 90° C. overnight. The reaction mixture was then partitionedbetween H₂O and EtOAc. The organic layer was dried and concentrated.Purification by silica gel chromatography (50-100%, EtOAc/CH₂Cl₂),followed by trituration with 1/1 hexane/acetone yielded1-ethyl-6-methoxy-5-morpholin-4-ylmethyl-2-(4-nitrophenyl)-1H-indole-3-carbonitrile(57 mg, 44% overall yield) as a yellow solid.

Example 1BO2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-1-cyclopropylmethyl-6-methoxy-1H-indole-3-carbonitrile(compound 716)

Step A: To a solution of 6-methoxyindole (5.88 g, 40.0 mmol) anddi-tert-butyl dicarbonate (9.59 g, 44.0 mmol) in DCM (50 mL) was added,at 40° C. while stirring, DMAP (0.10 g). After stirring overnight, themixture was washed sequentially with 0.1 N HCl, water and brine anddried over anhydrous Na₂SO₄. The solvent was evaporated and the residuewas chromatographed (silica gel, EtOAc/hexanes, 1/7) to providetert-butyl 6-methoxy-1H-indole-1-carboxylate (8.48 g, 86%).

Step B: The above Boc-indole (3.08 g, 12.5 mmol) and isopropylborate(4.83 mL, 21.9 mmol) were dissolved in anhydrous THF (20 mL) and thesolution was cooled at 0° C. While stirring, LDA (12.5 mL, 1.5 Mmono-THF complex in cyclohexane, 18.7 mmol) was added dropwise. Themixture was stirred at 0° C. for 15 min and then room temperature for0.5 hr, followed by the addition of HCl (6 N, 3.0 mL, 18 mmol) in aice-water bath. The organic solvent was removed in vacuo and the residuewas suspended in H₂O (100 mL) and acidified with HCl (6 N) to pH 4˜5.The precipitate was collected via filtration and washed with water andhexanes and dried in air to provide 1-Boc-6-mehoxyindole-2-boronic acid(3.38 g, 93%).

Step C: To a solution of 4-iodoanilline (3.18 g, 14.5 mmol) in pyridine(15 mL) at 0° C., was added 3-chloropropanesulfonyl chloride (2.3 mL,18.9 mmol). After the addition, the mixture was stirred for 2 hr at roomtemperature, and poured into ice-water (200 mL). The organic wasseparated and the aqueous layer was extracted with DCM (2×50 mL). Thecombined organics were washed with HCl (2 N, 2×15 mL), water (2×50 mL)and brine (20 mL) consecutively and dried over anhydrous Na₂SO₄. Thesolvent was then evaporated and the residue was chromatographed tofurnish 3-chloro-N-(4-iodophenyl)propane-1-sulfonamide (4.68 g, 90%).The chlorosulfonamide obtained (3.47 g, 9.6 mmol) was then treated withK₂CO₃ (3.33 g, 24.1 mmol) in DMF (50 mL) at 50° C. for 2 hr. The mixturewas poured into ice-water (300 mL) and the precipitate was collected anddried in air to provide essentially pure2-(4-iodophenyl)isothiazolidine-1,1-dioxide (3.11 g, 100%).

Step D: To a mixture of 1-Boc-6-mehoxyindole-2-boronic acid prepared instep B above (0.36 g, 1.25 mmol),2-(4-iodophenyl)isothiazolidine-1,1-dioxide (0.32 g, 1.0 mmol) andPdCl₂(dppf) (0.037 g, 0.05 mmol) in DMF (4.0 mL), was added aqueousK₂CO₃ solution (1.5 mL, 2.0 M, 3.0 mmol). The mixture was stirred atroom temperature overnight and then poured into ice-water (100 mL). Theprecipitate was collected and washed with water and purified by flashcolumn chromatography (silica gel, DCM/EtOAc, 9/1) to furnish1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole(0.43 g, 98%).

The following compound was made similarly: Compound 768

Step D:1-Boc-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1H-indole(1.63 g, 3.7 mmol) was treated with TFA (25 mL) in DCM (25 mL) at roomtemperature for 4 hr. After the removal of the volatiles, the residuewas carefully stirred with saturated NaHCO₃ for 0.5 hr. The precipitatewas collected via filtration and washed with water thoroughly and driedto provide essentially pure1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (1.17g, 92%).

Step E: At 0° C.,1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole (0.95g, 2.8 mmol) was dissolved in DMF (10 mL) and treated withchlorosulfonyl isocyanate (0.36 mL, 4.2 mmol). The mixture was thenstirred at room temperature overnight and poured into ice-water (150 mL)then stirred for 0.5 hr. The precipitate was collected via filtrationand washed thoroughly with water and dried in air to furnish1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile(0.89 g, 87%).

The following compound was prepared in the same fashion as describedabove: Compound 829

Step F: To a solution of1-H-2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxyindole-3-carbonitrile(73 mg, 0.2 mmol) and K₂CO₃ (69 mg, 0.5 mmol) in DMF (3.0 mL) was addedcyclopropylmethyl iodide (0.029 mL, 0.3 mmol). The mixture was stirredat 50° C. overnight and poured into ice-water (10 mL). The precipitatewas collected via filtration, washed with water and purified by columnchromatography to provide2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]-6-methoxy-1-cyclopropylmethylindole-3-carbonitrile,compound 716 (73 mg, 87%).

The following compounds were prepared in the same fashion as describedabove: Compounds 717, 718, 719, 782, 783, 784.

Example 1BP Preparation of2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole(compound 805)

Step A: 2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-indole (900mg, 2.62 mmol), prepared in example 1BO, step D was used to prepare2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole(608 mg, 60%), utilizing essentially the same procedure as example 1A,Step B.

Step B:2-[4-(1,1′-Dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-1-propyl-1H-indole(50 mg, 0.13 mmol) was used to prepare2-[4-(1,1′-dioxo-1λ⁶-isothiazolidin-2-yl)-6-methoxy-3-oxazol-5-yl-1-propyl-1H-indole(9 mg, 15% overall yield) according to the protocol in example 1P.

Example BQ Preparation of2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(compound 842)

Step A: To a solution of 1-ethyl-6-trifluoromethylindole-3-carbonitrile(2.54 g, 10.0 mmol), prepared by the method of procedure 1A, inanhydrous THF (20.0 mL), at −78° C. was added LDA (8.3 mL, 1.5 Mmono-THF in cyclohexane, 12.5 mmol) dropwise. The mixture was continuedfor 0.5 hr after the addition, followed by the addition ofhexachloroethane and the mixture was then brought to room temperatureslowly and stirred for 0.5 hr. The solvent was then evaporated and theresidue was treated with water. The organics were extracted withdichloromethane, washed with water and brine and dried over anhydrousNa₂SO₄. The crude product obtained after the removal of the solvent waschromatographed (silica gel, dichloromethane/hexanes, 3 /2) to provide2-chloro-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile (1.75 g,64%).

Step B: The chloroindole obtained above (0.27 g, 1.0 mmol), K₂CO₃ (0.35g, 2.5 mmol) and N-Boc-piperazine (0.28 g, 1.5 mmol) were stirred at 70°C. in DMF (5.0 mL) for 3 days and then poured into water (50 mL). Theprecipitate was collected via filtration and washed with water.Chromatography of this crude product (silica gel, dichloromethane/ethylacetate, 9/1) provided4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester, compound 785 (0.30 g, 71%).

The following compound was prepared in the same fashion as describedabove, by using other amines: Compounds 514, 785, 786.

Step C:4-(3-cyano-1-ethyl-6-trifluoromethyl-1H-indol-2-yl)-piperazine-1-carboxylicacid tert-butyl ester (0.26 g, 6.1 mmol) was treated with TFA (5 mL) indichloromethane (5 mL) for 1 hr at room temperature. After the removalof the volatiles, the residue was treated with saturated NaHCO₃ and theprecipitate was collected via filtration, washed with water thoroughlyand dried in air to furnish essentially pure1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(0.20 g, 100%).

Step D: To a solution of1-ethyl-2-piperazin-1-yl-6-(trifluoromethyl)-1H-indole-3-carbonitrile(32 mg, 0.1 mmol), pyridine (0.1 mL) in dichloromethaene (1.0 mL) wasadded cyclopropanesulfonyl chloride (28 mg, 0.2 mmol) and the mixturewas stirred at room temperature overnight. This was then diluted withdichloromethane (5 mL), washed with HCl (2 N, 2×2 mL), water (2×5 mL)and brine (5 mL) and chromatographed over silica gel(dichloromethane/ethyl acetate, 9/1) to provide2-[4-(cyclopropylsulfonyl)piperazin-1-yl]-1-ethyl-6-(trifluoromethyl)-1H-indole-3-carbonitrile,compound 842 (30 mg, 70%).

The following compounds were prepared in the same fashion as describedabove, using corresponding sulfonyl chlorides: Compounds 841, 843.

Example 1BR Ethanesulfonic acid[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-amide (compound 835)

Step A: 6-Bromo-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile(0.74 g, 2.0 mmol), compound 831, prepared from 6-bromoindole asdescribed in example 1Gb, was mixed with K₂CO₃ (0.55 g, 4.0 mmol), CuI(0.02 g, 0.1 mmol), tert-butyl carbamate (0.35 g, 3.0 mmol),N,N′-dimethylcyclohexane-1,2-diamine ligand (0.028 g, 0.2 mmol) andanhydrous toluene (5.0 mL) in a sealed tube. The reaction system wasflushed with nitrogen and then stirred at 110° C. overnight. Aftercooling, the solvent was replaced with dichloromethane andchromatographed (silica gel, dichloromethane) to provide[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-carbamic acidtert-butyl ester (0.68 g, 84%), compound 832.

Step B: Compound 832 prepared in step A above (0.63 g, 1.56 mmol) wastreated with TFA/DCM (7.5 mL/7.5 mL) at room temperature for 2 hr, andthe volatiles were removed in vacuum. The residue was treated withsaturated NaHCO₃ and the precipitate was collected via filtration andwashed thoroughly with water, dried in air to provide6-amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (0.45 g,96%), compound 833.

Step C: The above amine (31 mg, 0.1 mmol) was treated withethanesulfonyl chloride (19 mg, 0.15 mmol) in pyridine (1.0 mL) at roomtemperature overnight to provide, after purification using columnchromatography, ethanesulfonic acid[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-amide (83%),compound 835.

The following compound was prepared in the same fashion as describedabove: Compounds 830, 834, 836 and 837.

Example 1BS Preparation of[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethylester (compound 838)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1mmol), compound 833, prepared in example 1BR, step B was treated withethyl chloroformate (16 mg, 0.15 mmol) in pyridine (1.0 mL) at roomtemperature overnight to furnish, after purification using columnchromatography[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-carbamic acid ethylester (30 mg, 79%).

Example 1BT Preparation of1-[3-cyano-2-(4-ethoxyphenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea(compound 839)

6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1mmol) was treated with ethyl isocyanate (14 mg, 0.2 mmol) indichloromethane (1.0 mL) at 40° C. overnight. The precipitate wascollected via filtration, washed with dichloromethane an dried in air tofurnish,1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (36mg, 95%).

Example 1BU Preparation of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea(compound 442)

To solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (50 mg,0.172 mmole) in THF (2 mL) was added 2-chloroethyl isocyanate (22 uL,0.258 mmole) at room temperature. After stirring overnight at reflux,the reaction mixture was concentrated in vacuo and the residue wasdiluted with ethyl acetate. The resulting semi-solid was triturated withhexane and the precipitate collected was collected by filtration andwashed well with 50% ethyl acetate in hexane and dried in vacuo toafford (62 mg, 91%) of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea.

Utilizing essentially the same procedure, the following compounds wereprepared: Compounds 295, 362, 395, 396, 397, 398, 399, 400, 401, 402,403, 404, 405, 406, 407, 443, 444, 445, 446, 511, 512, 513, 600, 620,626, 627, 628, 679, 680, 681, 740, 741, 742, 743, 748, 749, 750, 751,774, 817, 818, 846, 847, 848.

Example 1BV Preparation of1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile(compound 771)

To a solution of1-(2-chloroethyl)-3-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-urea(100 mg, 0.252 mmol) in MeOH (10 mL) was added aqueous 1M KOH (504 uL)and then stirred at 49° C. for 24 h. The solvents were removed underreduced pressure. The residue was diluted with ethyl acetate and thenwashed with water. The organic layer was dried over anhydrous MgSO₄,filtered and concentrated under reduced pressure. The residue wasdiluted with ethyl acetate and then triturated with hexane and theprecipitate collected by filtration and washed well with 50% ethylacetate in hexane and dried in vacuo to afford1-ethyl-6-methoxy-2-[4-(2-oxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carbonitrile(56 mg, 62%).

Using essentially the same procedure, the following compounds wereprepared: Compounds 770, 778

Example 1BW Preparation of1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile(compound 638)

To a solution of[4-(3-cyano-1-ethyl-6-isopropoxy-1H-indol-2-yl)-phenyl]-carbamic acid2-chloro-ethyl ester (30 mg, 0.07 mmol) in DMF (1 mL) was added aqueousK₂CO₃ (10 mg) and then stirred at 50° C. for 18 h. The reaction mixturewas poured into cold water and the precipitate collected by filtrationand washed with hexane and dried in vacuo to afford the title compound(21 mg, 81%).

The following compounds were made in similar fashion: Compounds 820,821, 863, 864.

Example 1BX Preparation of{3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid ethyl ester (compound 530)

Step A: To a solution of[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.65 g, 4.37 mmole) in DCM (20 mL) was added 1M BBr₃ in DCM(13.12 mL) over a period of 20 min. The reaction mixture was stirredfurther 1 h at room temperature and then the solvents were removed underreduced pressure. The residue was dissolved in MeOH and then poured intocold water. The precipitate was collected by filtration and washed withhexane and dried in vacuo to afford[3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.5 g, 98%).

Step B: To a solution of[3-(3-cyano-1-ethyl-6-hydroxy-1H-indol-2-yl)-phenyl]-carbamic acid ethylester (1.2 g, 2.91 mmol) in DMF (10 mL) was added K₂CO₃ (538 mg, 3.9mmole) and 3-bromo-1-chloroproane (383 uL, 3.9 mmole) and the reactionwas stirred for overnight at 50° C. The reaction mixture was then pouredinto cold water and the precipitate was collected by filtration andwashed with hexane and dried in vacuo to afford 1.1 g, 89% of thedesired product.

Step C: To a solution of{3-[3-cyano-1-ethyl-6-(3-pyrrolidin-1-yl-propoxy)-1H-indol-2-yl]-phenyl}-carbamicacid ethyl ester (50 mg, 0.12 mmole) in CH₃CN (2 mL) was added DIEA (31uL, 0.18 mmol), sodium iodide (20 mg, 0.132 mmol) and pyrrolidine (30uL, 0.36 mmole). The resulting mixture was stirred at reflux temperaturefor overnight. The solvent was evaporated and the residue was dilutedwith ethyl acetate and then triturated with hexane and the precipitatecollected by filtration and washed well with 50% ethyl acetate in hexaneand dried in vacuo to afford1-ethyl-6-isopropoxy-2-[4-(2-oxo-oxazolidin-3-yl)-phenyl]-1H-indole-3-carbonitrile,compound 638 (46 mg, 85%).

The following compounds were made in similar fashion following stepsA-C, above: Compounds 441, 447, 491, 492, 493, 504, 525, 526, 527, 528,529, 531, 532, 533, 534, 535, 536, 537, 538, 539

Example 1BY Preparation of[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea (Compound767)

Step A: The starting material2-(3-amino-phenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (187 mg,0.642 mmol) was dissolved in anhydrous acetone (3.0 mL). Benzoylisothiocyanate (107 mg, 0.656 mmol) was added to the solution at roomtemperature and the mixture was stirred for 17 h during which time aprecipitate had formed. The precipitate was filtered, washed withacetone and dried to give 264 mg of1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea(90% yield) as a light yellow solid.

Step B: A suspension of1-benzoyl-3-[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea(241 mg, 0.530 mmol) in methyl alcohol (2.0 ml) and water (0.5 mL) wasstirred at room temperature as sodium hydroxide (31 mg, 0.78 mmol) wasadded. The reaction mixture was heated to 50° C. for 17 h. The reactionmixture was concentrated to remove methyl alcohol. Water was added tothe mixture and the solid was filtered, washed with water and dried togive 179 mg of[3-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-thiourea, compound767 (96% yield) as a white solid.

Example 1BZ Preparation of1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile(Compound 458)

A solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (100 mg,0.343 mmol), 4-chloro-2-phenyl-quinazoline (83 mg, 0.34 mmol) anddiisopropylethylamine (0.10 mL, 0.57 mmol) in absolute ethanol (3 mL)was heated to reflux overnight. The solution was cooled and evaporated,and the residue taken up in ethyl acetate (50 mL). This was washed withwater and saturated brine (50 mL each), then dried over anhydrous sodiumsulfate, filtered and evaporated. The resulting solid was trituratedwith ether, collected by filtration and dried under vacuum to afford1-ethyl-6-methoxy-2-[4-(2-phenylquinazolin-4-ylamino)-phenyl]-1H-indole-3-carbonitrile(139 mg, 0.280 mmol, 82%).

Example 1CA Preparation of diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate(compound 772)

A solution of2-(4-aminophenyl)-6-ethoxy-1-ethyl-1H-indole-3-carbonitrile (148 mg,0.484 mmol), diethyl chlorophosphate (0.086 mL, 0.58 mmol) anddiisopropylethylamine (0.10 mL, 0.57 mmol) in 1,4-dioxane (5 mL) wasstirred at ambient temperature for 12 hours, then heated to 80° C. foran additional 24 hours. The solution was cooled and poured into 50 mL ofethyl acetate. This was washed with water and saturated brine (50 mLeach), then dried over anhydrous magnesium sulfate, filtered andevaporated. The residual material was separated by flash chromatography(eluting 2/1 ethyl acetate/hexane on silica gel 60) to afford diethyl[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-phosphoramidate (108mg, 0.245 mmol, 51%) as a white powder after evaporation.

Example 1CB Preparation of1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile(compound 726)

Step A: To a solution of2-(4-aminophenyl)-1-ethyl-6-methoxy-1H-indole-3-carbonitrile (202 mg,0.693 mmol) in pyridine (2.0 mL) was added theN-β-(chloroethylamino)sulfonyl chloride (222 mg, 1.39 mmol). The mixturewas stirred at room temperature for 17 h then water (12.0 mL) was addedand the mixture was extracted with ethyl acetate (3×2 mL). The extractwas washed with 10% aqueous HCl (2×2 mL), water (2×2 mL), dried overMgSO₄, filtered and concentrated on a rotary evaporator. The crudeproduct was purified by flash chromatography (0-5%, ethylacetate/methylene chloride) to give 217 mg ofN-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide, compound 724, as a tan solid (75% yield).

In similar fashion the following compounds were prepared: Compounds 540,541, 542, 574, 576, 704

Step B: To a solution ofN-(2-chloro-ethyl)-N′-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)phenyl]sulfamide (100 mg, 0.241 mmol) in anhydrous DMF (1.25 mL), was addedpotassium carbonate (71.0 mg, 0.514 mmol). The mixture was stirred atroom temperature for 17 h, then diluted with water (7.5 mL). Thereaction mixture was extracted with ethyl acetate (3×2 mL) and theextract was washed with water (2×2 mL), dried over MgSO₄ andconcentrated to give2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile,compound 725, as a white solid (84 mg, 88% yield).

In similar fashion the following compound was prepared: Compound: 705

Step C: To a solution of2-[4-(1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)phenyl]-1-ethyl-6-methoxy-1H-indole-3-carbonitrile(34 mg, 0.086 mmol) in anhydrous DMF (1.0 mL) was added potassiumcarbonate (25 mg, 0.18 mmol) and iodomethane (20.4 mg, 0.144 mmol). Themixture was stirred at room temperature for 2 h. and then diluted withwater (6.0 mL) to give a precipitate. The precipitate was filtered,washed with water and dried to give1-ethyl-6-methoxy-2-[4-(5-methyl-1,1-dioxo-1λ⁶-[1,2,5]thiadiazolidin-2-yl)-phenyl]-1H-indole-3-carbonitrile,compound 726, as a white solid (35 mg, 98% yield).

In similar fashion the following compound was prepared: Compound 727.

Example 2 Screening of Low Molecular Weight Compounds Using a Cell-BasedHCV IRES Monocistronic Translation Assay

Chemical libraries are screened using a cell-based monocistronic HCVIRES-regulated translation assay designed to closely mimic natural HCVmRNA translation and then compound analogs are made based on hits in thechemical libraries and screened as well. A DNA construct is prepared,termed pHCVIRESmono, in which HCV IRES sequences (HCV 2b, nucleotides18-347) are inserted between a promoter and the firefly luciferase(Fluc) reporter gene. A stably transfected HepG 2 (hepatoblastoma) cellline (termed HepGmono-4) or a Huh7 cell line (termed Huhmono 7), or aHela-cell line (termed Helamono), are established by transfection withthe pHCVIRESmono DNA by selecting for resistance to hygromycin.

Example 3 Determination of Selectivity for HCV IRES-RegulatedTranslation Using the Cell-Based Cap-Dependent Translation Assays

Since translation assays are used to screen HCV IRES inhibitors, theselected hits may specifically act on HCV IRES-driven translation or maymodulate general protein synthesis in mammalian cells. The compoundsthat act on general translation will most likely have significanttoxicity. To address this possibility, various cell-based cap-dependenttranslation assays are established for the further evaluation of allselected compounds. Plasmid DNAs containing 130 nucleotides of vectorsequence 5′ to Fluc are constructed. This construct is referred toherein as pLuc. A stable cell line is established in cap-dependenttranslation assays using 293T cells (a human embryonic kidney cellline). HepGmono-4 and pLuc are treated with compound for 20 hours andactivity is determined by quantifying the Fluc signal. A five-foldselectivity between the HCV IRES and cap-dependent translation isconsidered to be desirable. For example, using these cell-basedcap-dependent translation assays, Applicants identified compounds thatshowed IC₅₀ values that were at least 5-fold greater in thecap-dependent translation assays than in the HCV IRES translation assay.FIG. 1 shows an example of a hit that was selective against HCVIRES-regulated translation over cap-dependent pLuc translation.Importantly, the compound had the same level of activity in an HCV IRESmonocistronic 293T cell line as in HepGmono-4 (data not shown). It isthus unlikely that the selectivity of the compounds between HepGmono-4(HepG 2) and the cap-dependent translations (293T) is due to thedifferent cell types used.

Additionally, western blotting assays are used to further demonstratethat the compounds selectively inhibit HCV IRES-driven translation. BothHepGmono-4 and pLuc cells are treated with the compounds as describedabove, following treatment with the test compounds for 20 hours, cellsare collected and lysed in Laminin buffer containing 0.5% SDS. Proteinsare separated on a 10% SDS-PAGE, then transferred onto a nitrocellulosemembrane, and blotted using antibodies against Fluc (RDI) and β-actin(Oncogene). For example, some of the compounds of the present inventionwere tested in this manner and as expected, the compounds thatselectively inhibited HCV IRES-driven translation in assays using Flucsignal as an end point showed comparable reductions of the luciferasereporter protein levels in HepGmono-4 cells and were relatively inactiveagainst pLuc in the Western blot (data not shown). Importantly, thesecompounds did not inhibit the expression of endogenous β-actin, thetranslation of which is cap-dependent in both cell lines. Consistently,compounds that did not show selectivity in the translation assaysinhibited protein accumulation in both the HCV IRES and cap-dependenttranslation assays (data not shown). As expected, the general proteintranslation inhibitor puromycin also inhibited both the HCV IRES-drivenand cap-dependent protein production (data not shown). Therefore, theWestern blot results confirm that the compounds of the present inventionselectively inhibit HCV IRES-driven translation.

Testing conditions for these cell lines are optimized and the effects ofmRNA level on activity of the compounds are controlled by quantitatingFluc mRNA levels by RT real-time PCR. For example, some of the compoundsof the present invention were tested in this manner, and no significantdifferences in Fluc mRNA levels were observed between the HepGmono-4, orthe Helamono cells, or the Huhmono cells, and cap-dependent translationcell lines used (data not shown).

Example 4 Evaluation of the Selectivity for HCV IRES-Driven TranslationUsing Cellular IRES-Mediated Translation Assays

A number of human mRNAs have been shown to harbor IRES elements (18, 19,39, 44, 45, 91, 126, 130). Although the primary sequences and secondarystructures of the HCV IRES are different from those of cellular IRESs,an important test for selectivity is to determine whether the selectedcompounds are active against cellular IRESs. The VEGF IRES has poorinitiation activity in in vitro assays, but demonstrates substantialactivity in cell-based translation assays (18, 45). For example, some ofthe compounds of the present invention were tested and all of thecompounds that had good selectivity with respect to cap-dependenttranslation exhibited at least 5-fold higher IC₅₀ values against theVEGF IRES than against the HCV IRES (data not shown). These dataindicate that the selected compounds have selectivity against viralIRES. In addition to having different structures, the VEGF IRES alsohave different interactions with non-canonical cellular translationfactors. These differences may contribute to the selectivity of the HCVIRES inhibitors that we have identified.

Example 5 Evaluation of Cytotoxicity

Effects on cell proliferation are a critical issue for any drugdiscovery effort. Therefore, a cell proliferation/cytotoxicity assay isused to eliminate any compounds that affect mammalian cell growth. Theeffects of the selected hits on cell proliferation are tested in humancell lines 293 T and Huh7 (a human hepatoblastoma cell line). Cells aregrown in Dulbecco's modified Eagle's medium supplemented with 10% fetalbovine serum, L-glutamine, penicillin, and streptomycin. Cells in logphase are treated with test compounds for three days, with 250 μM beingthe highest concentration of test compound used. The effect of thecompounds on cell proliferation is assessed by using the CellTiter 96AQueous One Solution Cell Proliferation Assay (Promega, Madison, Wis.).Compounds that have at least 5-fold higher CC₅₀ values relative to IC₅₀values in HepGmono-4 are considered to have a sufficient window betweenactivity and cytotoxicity and, hence, are selected for furtherevaluation. For example, some of the compounds of the present inventionwere tested in this manner, and importantly, all compounds that had goodselectivity with respect to cap-dependent translation also demonstrateda greater than 5-fold ratio of CC₅₀ to IC₅₀ values.

Example 6 Evaluation of the Efficacy of the Compounds in the HCVReplicon System

The lack of reliable and readily accessible cell-culture and smallanimal models permissive for HCV replication has limited the developmentof new anti-HCV agents. Self-replicating subgenomic HCV systems, termedHCV replicons, have recently been described and have been widely used toassess the efficacy of anti-HCV inhibitors (8, 70, 104). Interferon(IFN) α and inhibitors of the HCV protease and polymerase have beenreported to be active in the HCV replicon system (8, 17, 32, 68, 69,117).

HCV replicons that include bicistronic and monocistronic systems areidentified and assays for testing the HCV IRES inhibitors areestablished. In the bicistronic replicons, the HCV IRES directs theexpression of the selective marker (Neo and/or a Fluc reporter), and theEMCV IRES mediates the expression of viral non-structural proteins. Inthe monocistronic replicon, the HCV IRES directly mediates viral proteinsynthesis. The HCV IRES inhibitors are analyzed in the bicistronicreplicon by quantitating the Fluc reporter signal. Replicon-containingcells are cultured with the compounds of the invention for 2 days.Interferon (IFN) α is used as a positive control. For example, thecompounds of the present invention were tested in this manner, and theexperiments showed that compounds that selectively inhibited HCVIRES-mediated translation inhibited Fluc expression in the bicistronicreplicon.

In the following table (Table 1),

-   -   * =Replicon or HCV-PV IC50>2μM    -   ** =Replicon or HCV-PV IC50 between 0.5 μM and 2 μM    -   *** =Replicon or HCV-PV IC50<0.5 μM

-   Replicon IC50 values are determined by firefiy luciferase signal.

-   HCV-PV IC50 values are determined by viral RNA reduction.

TABLE 1 Mass Compound Melting Spec HCV-PV Replicon Number Point (° C.)[M+H] IC50 μM IC5Os μM NMR Data 1 * 2 311.1 * 3 356.0 * 4 279.2 * 564-66 201.3 * 6 201.1 * 7 304-305 251.1 ** ¹H NMR (300 MHz, DMSO-d₆): δ8.23 (1H, d, J=2.1 Hz), 8.08 (1H, dd, J=8.8, 2.1 Hz), 7.74 (1H, d, J=8.8Hz), 7.55 (2H, t, J=2.2 Hz), 6.51 (2H, t, J=2.2 Hz). 8 277.3 ** 9 61-63215.2 * 10 69-71 229.2 * 11 78-80 243.2 * 12 94-97 277.2 ** 13 161-164265.3 * 14 206-207 415.2 * ¹H NMR (300 MHz, CDCl₃): δ 8.09 (1H, dd,J=8.8, 1.7 Hz), 7.75 (1H, d, J=1.7 Hz), 7.49 (1H, d, J=8.8 Hz),Hz 7.40(2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 6.93(2H, d, J=8.8 Hz), 6.15 (1H, s), 3.93 (3H, s), 3.83 (3H, s). 15 225-226290.3 * 16 175-177 286.3 * 17 248.1 * 18 237.3 * 19 307.4 * 20 159-160267.2 * 21 125-125 277.3 * 22 146-149 321.1 ** 23 234-235 334.2 *** 24123-124 307.1 ** 25 291-293 271.2 * ¹H NMR (300 MHz, DMSO-d₆): δ 10.81(1H, s), 8.63 (1H, d, J=1.7 Hz), 8.10 (1H, dd, J=8.8, 1.7 Hz), 7.76 (1H,d, J=8.8 Hz), 4.35 (2H, q, J=7.0 Hz), 2.22 (3H, s), 1.26 (3H, t, J=7.0Hz). 26 287-288 335.3 ** ¹H NMR (300 MHz, CDCl₃): δ 10.83 (1H, s), 8.23(1H, s), 8.00 (1H, d, J=8.8 Hz), 7.92 (2H, d, J=7.3 Hz), 7.60 (1H, d,J=8.5 Hz), 7.53-7.43 (1H, m), 7.41-7.30 (2H, m), 4.12 (2H, q, J=7.3 Hz),1.31 (3H, t, J=7.3 Hz). 27 138-140 236.3 ** 28 68-70 272.2 ** 29 oil284.3 * 30 114-116 292.2 * ¹H NMR (300 MHz, DMSO-d₆): δ 8.19 (1H, d,J=2.3 Hz), 7.96 (1H, dd, J=8.8, 2.3 Hz), 7.69 (1H, d, J=8.8 Hz), 7.38(1H, t, J=7 Hz), 4.32 (2H, q, J=7.0 Hz), 3.81 (3H, s), 3.61 (2H, pentet,J=7 Hz), 1.29 (3H, t, J=6.7 Hz), 1.24 (3H, t, J=7.0 Hz). 31 189-190264.1 * ¹H NMR (300 MHz, DMSO-d₆): δ 8.11 (1H, d, J=2.0 Hz), 7.94 (1H,dd, J=8.5, 2.0 Hz), 7.65 (1H, d, J=8.5 Hz), 7.54 (2H, br s), 4.21 (2H,q, J=7.0 Hz), 3.79 (3H, s), 1.20 (3H, t, J=7.0 Hz). 32 oil 280.2 * 33113-117 280.2 * 34 137-141 232.1 * 35 318-319  411.0, * ¹H NMR (300 MHz,DMSO-d₆): 413.0 δ 11.29 (1H, s), 8.71 (1H, d, [M-H] J=2.0 Hz), 8.13 (1H,dd, J=8.8, 2.0 Hz), 7.98 (2H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz), 7.83(1H, d, J=8.8 Hz), 4.41 (2H, q, J=7.0 Hz), 1.28 (3H, t, J=7.0 Hz). 36273-274 380.1 * ¹H NMR (300 MHz, DMSO-d₆): δ 11.58 (1H, s), 8.87 (1H,s), 8.72 (1H, s), 8.53 (1H, d, J=7.0 Hz), 8.47 (1H, d, J=7.0 Hz), 8.14(1H, d, J=8.5 Hz), 7.91 (1H, t, J=8.2 Hz), 7.86 (1H, d, J=8.8 Hz), 4.45(2H, q, J=7.0 Hz), 1.30 (3H, t, J=7.0 Hz). 37 56-60 246.2 * 38 96-100310.1 * 39 94-98 310.1 * 40 176-180 269.1 * 41 155-175 267.1 * 42138-143 296.1 * 43 229.2 * 44 293.2 * 45 130-131 215.5 * 46 376.2 * 47140-145 376.2 * 48 138-142 296.3 ** 49 89-90 376.3 * 50 91-92 259.3 * 5195-96 229.4 52 243.2 * 53 145-147 363.1 ** 54 99-101 272.3 * 55 183-185292.2 * 56 223-224 301.2 ** 57 130-133 243.2 58 76-79 243.2 * 59 81-85242.2 * 60 133-136 271.2 * 61 153-158 270.2 * 62 262.0 * 63 188-192333.4 * 64 108-113 301.3 * 65 130-132 331.3 ** 66 119-122 331.3 * 67132-136 319.3 ** 68 140-147 315.3 ** 69 163-166 316.3 ** 70 142-141321.2 * 71 199.4 348.2 * 72 144-149 271.3 * 73 oil 259.2 * 74 179-182325.3 * 75 118-123 271.3 * 76 118-120 293.3 * 77 117-118 307.3 * 78110-114 287.2 * 79 257-260 332.4 * 80 292-294 356.5 ** 81 209-211 360.5*** *** 82 223-228 372.5 *** ** 83 221-223 384.4 *** *** 84 232-237396.4 *** *** 85 163-165 398.3 *** *** 86 158-160 410.3 *** 87 187-189396.3 *** *** 88 209-213 398.4 *** ** 89 148-155 308.3 ** 90 80-95364.4 * 91 160-161 301.2 92 155-156 317.2 * 93 172.4-172.6 305.3 * 94262-265 314.4 ** 95 248-251 344.4 ** 96 243-250 329.4 ** 97 164-167350.4 * 98 180-185 363.2 * 99 123.4-123.8 307.0 * 100 128-129 277.2 *101 204-209 426.6 ** 102 136.7-136.9 267.2 * 103 90-93 263.2 * 104190-194 406.4 ** 105 204-206 442.4 * 106 230-243 494.4 * 107 157-158327.1 * 108 94-96 249.2 * 251.2 109 54-56 263.2 * 265.2 110 128-130349.3 ** 111 208.5 374.3 * ¹H NMR (CDCl₃, 400 MHz), δ = 7.75-7.72 (m,2H), 7.13-7.10 (m, 2 H), 6.97-6.88 (m, 3H), 6.11 (s, 2H) 112 173.1-173.5277.3 ** ¹H NMR (CDCl₃, 400 MHz), δ = 7.67 (t, J=8.4 Hz, 2 H), 7.24 (d,J=14.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1 H), 6.96-6.90 (m, 3 H), 6.10 (s, 2H), 2.46 (s, 3 H) 113 193-194 374.3 * 114 207-298 390.3 * 115 175-177177.1 * 116 116-118 349.4 * 117 120-123 249.3 * 118 62-65 205.2 ** 119126-128 283.2 ** 120 69-71 205.5 * 121 167-169 364.5 ** 122 163-169426.5 * 123 113-117 239.4 * 124 212.2-212.3 291.3 * CDCl₃, 400 MHz, δ =7.61 (dd, J=8.4 Hz and 4.4 Hz, 1 H), 7.04-6.96 (m, 2H), 6.77 (m, 3H),6.12 (s, 2H), 2.42 (s, 3H) 125 151.2-151.7 291.3 ** CDCl₃, 400 MHz, δ =7.57 (d, J=8.0 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.97 (d, J=28.0 Hz, 1H), 6.86 (s, 1 H), 6.79 (dd, J=11.2 Hz and 2.0 Hz, 2H), 6.12 (s, 2H),2.42 (s, 3H), 2.40 (s, 3H) 126 146-148 251.3 * 127 173-175 327.3 * 128218-220 334.5 * 129 188-190 370.4 ** 130 227-233 394.5 *** 131 199-204408.5 ** 132 209-212 422.5 ** 133 144-146 351.5 ** 134 155-157 335.4 **135 168-170 369.5 ** 136 159-161 381.4 ** 137 129-132 345.5 ** 138235-239 358.5 *** ** 139 191-195 388.5 *** ** 140 83-96 253.3 * 141145-146 253.4 * 142 103-105 237.4 * 143 168-171 384.5 * 144 97-100 315.4** 145 110-113 357.5 ** 146 169-172 335.3 ** 147 183-186 344.4 ** 148155-157 335.4 ** 149 134-136 345.4 ** 150 141-143 319.4 ** 151 146-148319.4 ** 152 207-211 386.5 * 153 225-228 398.5 * ** 154 293.1 ** DMSO,400 MHz, δ = 8.13 (d, J=6.4 Hz, 1H), 8.01 (s, 2H), 7.84 (s, 1H), 7.54(dd, J=12.4 Hz and 3.6 Hz, 1H), 7.15 (d, J=8.8 Hz, 2H), 3.83 (s, 3H) 155** CDCl₃, 300 MHz, δ = 9.31 (s, 1H), 8.32 (s, 1H), 8.19-8.17 (m, 1H),7.75 (s, 1H), 2.70 (s, 3H) 156 205-209 421.5 ** 157 149-153 422.5 ** 158153-156 317.5 ** 159 147-150 361.3 ** 160 117-119 315.7 ** 161 174-176340.3 ** 162 185-190 413.5 * 163 235-239 410.5 ** 164 273-280 358.5 **165 211-225 373.5 * 166 236-240 385.5 *** 167 196-200 464.5 ** 168199-204 394.5 * 169 147-150 316.5 ** 170 148-151 307.4 ** 171 134-137307.4 ** 172 221-223 317.4 ** 173 150-153 316.5 ** 174 139-142 302.4 **175 132-135 359.5 ** 176 162-164 343.5 ** 177 125-130 331.4 ** 178119-123 369.4 * 179 79-80 239.4 ** 180 170-171 384.5 ** ** 181 177-178398.5 ** 182 148-154 408.5 *** 183 276-284 344.5 ** 184 197-200 337.4 **185 157-160 355.4 ** 186 166-169 317.4 ** 187 187-191 321.4 ** 188209-212 287.4 ** 189 252-253 356.4 * 190 234-236 370.4 ** 191 208-210370.4 ** * 192 205-207 384.5 ** 193 228-232 378.5 ** [M-H] ** 194278-284 370.4 ** 195 271-275 398.4 ** 196 187-189 354.3 ** 197 147-149373.6 * 198 163-165 395.7 * 199 156-158 369.2 *** * 200 187-189 354.4 **201 147-150 381.2 ** 202 137-139 369.4 ** 203 257.9 ** DMSO, 300 MHz, δ= 10.34 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.87(dd, J=8.7 Hz and 2.1 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.80 3.80 (s,3H), 2.12 (s, 3H), 1.21 (t, J=7.2 Hz,3H) 204 320.1 *** DMSO, 300 MHz, δ= 10.81 (s, 1H), 8.02 (t, J=7.2 Hz, 2H), 7.67-7.47 (m, 4H), 7.21 (d,J=2.4 Hz, 1H), 6.90 (dd, J=8.4 Hz and 2.1 Hz, 1H), 4.12 (q, J=6.9 Hz,2H), 3.83 (s, 3H), 1.24(t, J=27.5 Hz, 3H) 205 181-184 358.4 ** 206187-191. 372.4 ** 207 179-183. 386.4 ** 208 192-194. 394.4 ** 209180-183. 408.4 ** 210 213-216 422.4 ** 211 186-191. 384.4 ** 212 180-183400.4 ** 213 165-168 398.4 ** 214 254.8-255.1 338.1 *** ¹H NMR (DMSO,300 MHz), δ = 7.88 (d, J=7.5 Hz, 1H), 7.82 (d, J=9.9 Hz, 1H), 7.64 (q,J=8.1 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.56-7.48 (m, 2H), 7.21 (d, J=2.1Hz, 1H), 6.91 (dd, J=8.7 Hz and 2.1 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H),4.13 (s, 3H), 1.23 (t, J=6.9 Hz, 3H) 215 245-246 345.1 ** ¹H NMR (DMSO,300 MHz), δ = 11.08 (s, 1H), 8.16 (d, J=8.4 Hz, 2H), 8.07 (d, J=7.8 Hz,2H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 6.91 (dd, J=8.4 Hzand 1.8 Hz, 1H), 4.08 (q, J=2.1 Hz, 2H), 3.80 (s, 3H), 1.25 (t, J=7.2Hz, 3H) 216 261 283.9 ** ¹H NMR (DMSO, 300 MHz), δ = 10.58 (br, 1H),7.42 (d, J=8.7 Hz, 1H), 7.15 (d, J=2.1 Hz, 1H), 6.86 (dd, J=8.7 Hz and2.4 Hz, 1H), 4.08 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 2.04 (br, 1H), 1.21(t, J=6.9 Hz, 3H), 0.89-0.84 (m, 5H) 217 272-273 315.9 *** ¹H NMR (DMSO,300 MHz), δ=9.94 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.15 (d, J=2.1 Hz,1H), 6.87 (dd, J=8.7 Hz and 2.4 Hz, 1H), 4.12 (q, J=7.2 Hz, 2H), 3.91(d, J=6.6 Hz, 2H), 3.80 (s, 3H), 1.89-1.92 (m, 1H), 1.21 (t, J=7.2 Hz,3H), 0.89 (d, J=6.6 Hz, 6H) 218 174-177 344.3 ** 219 145-149 388.4 **220 219-223 387.7 ** 221 195-200 421.3 ** 222 216-219 385.4 ** 223210-216 316.4 ** 224 245-249 358.3 ** 225 231-236 372.3 ** 226 294-295375.9 * ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 3.72 (s, 3H), 3.80 (s, 3H),6.75-6.91 (m, 2H), 7.42-7.56 (m, 2H), 8.04 (d, 1H), 8.23 (d, 1H), 8.67(d, 1H). 227 198-203 392.3 ** 228 195-198 388.3 * 229 142-147 321.3 *230 218-220 323.4 * 231 201-203 289.3 * 232 190-193 307.3 * 233 232-234329.4 ** 234 221-223 288.3 * 235 218-222 316.4 ** 236 145-147 287.3 *237 146-148 303.3 * 238 189-191 273.3 * 239 212-218 292.3 * 240 164-167335.3 * 241 184-188 344.3 * 242 242-248 334.3 * 243 194-198 370.3 ***244 187-190 360.4 . 245 192-195 390.4 * 246 160-164 374.4 * 247 212-217293.3 * 248 117-121 351.4 ** 249 132-136 337.4 ** 250 160-162 323.3 *251 186-187 398.4 *** ** 252 176-177 432.4 ** 253 121-125 399.2 ** 254153-154 307.21 * 255 149-151 435.5 ** 256 230-232 331.3 * 257  174-176.330.3 * 258 146-148 330.3 * 259 foam 358.3 * 260 109-111 359.3 * 261138-143 406.4 ** 262 117-121 365.4 ** 263 121-127 419.4 ** 264 glass406.5 ** 265 204-206 355.3 * 266 96-99 362.4 ** 267 106-112 336.4 268137-143 414.4 ** 269 153-158 428.4 ** 270 175-177 404.4 * 271 158-160418.4 ** 272 173-176 396.4 ** 273 207-209 404.4 * 274 166-172 378.4 *275 201-206 384.4 * 276 224-228 426.4 * 277 186-191 370.4 * 278 234-240356.4 * 279 197-202 407.5 * 280 89-95 364.4 * 281 132-134 283.3 * 282135-136 317.3 * 283 215-218 353.4 * 284 112-114 267.3 * 285 185-190420.5 * 286 191-192 333.3 ** ¹H NMR (300 MHz, CDCl₃): δ 7.92-7.88 (2H,m), 7.67 (1H, s), 7.66 (1H, d, J=8.8 Hz), 7.46-7.42 (2H, m), 6.98 (1H,dd, J=8.8, 2.3 Hz), 6.88 (1H, d, J=2.3 Hz), 4.35 (2H, q, J=7.3 Hz), 3.92(3H, s), 1.46 (3H, t, J=7.3 Hz). 287 175-177 384.4 * 288 194-199 293.3 *289 173-175 432.2 * 290 433.1 * ¹H NMR (CDCl₃, 300MHz), δ7.97-7.92 (m,2H), 7.70-7.62 (m, 3H), 7.10 (br, 1H), 6.98 (dd, J=8.7 Hz and 2.1 Hz,1H), 6.88 (d, J=2.1Hz, 1H), 4.16 (q, J=7.5 Hz, 2H), 3.91 (s, 3H), 3.77(t, J=4.2 Hz, 4H), 3.62 (q, J=5.4Hz, 2H), 2.68 (t, J=5.7 Hz, 2H), 2.59(br, 4H), 1.36 (t, J=7.2 Hz, 3H) 291 319.9 * ¹H NMR (CD₃OD, 300MHz), δ8.07 (d, J=7.2 Hz, 2H), 7.79-7.68 (m, 2H), 7.54 (d, J=8.7 Hz, 1H), 7.12(d, J=2.1 Hz, 1H), 6.97 (dd, J=8.7 Hz and 2.1 Hz, 1H), 4.24 (q, J=7.5Hz, 2H), 3.90 (s, 3H), 1.26 (t, J=7.2 Hz, 3H) 292 176-177 348.0 * ¹H NMR(CDCl₃, 300 MHz), δ 7.93- 7.88 (m, 2H), 7.69-7.60 (m, 3H), 6.98 (dd,J=8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 6.17 (br, 1H), 4.15(q, J=7.2 Hz, 2H), 3.91 (s, 3H), 3.53 (m, 2H), 1.35 (t, J=7.2 Hz, 3H),1.28 (t, J=7.2 Hz, 3H) 293 412.5 * 294 364.4 *** 295 609.4 ** 296 392.4** 297 378.4 ** 298 394.4 ** 299 376.4 ** 300 392.4 ** 301 412.4 ** 302382.4 ** 303 374.2 * 304 426.4 ** 305 442.4 * 306 446.4 ** 307 430.4 **308 424.3 * 309 490.3 ** 310 378.4 ** 311 392.1 * 312 378.1 * 313394.1 * 314 376.1 * 315 412.0 * 316 474.1 * 317 382.1 * 318 446.1 * 319430.1 * 320 426.1 * 321 490.9 * 322 223-230 308.4 * 323 102.9-103.4447.2 * ¹H NMR (CD₃OD, 300 MHz), δ8.02-8.00 (m, 2H), 7.78-7.68 (m, 2H),7.55 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J=6.6 Hz and 1.5Hz, 1H),4.24 (q, J=7.5Hz, 2H), 3.90 (s, 3H), 3.68 (t, J=4.2Hz, 4H), 3.52 (q,J=5.4Hz, 2H), 2.50 (t, J=6.9Hz, 6H), 1.86 (br, 2H), 1.28 (t, J=7.2Hz,3H) 324 165.3-165.7 368.1 * (DMSO, 300 MHz), δ 10.56 (s, 1H), 7.85 (s,1H), 7.73 (d, J=7.8 Hz, 1H), 7.54 (q, J=7.8 Hz, 2H), 7.31 (d, J=7.8 Hz,1H), 7.23 (s, 1H), 6.92 (d, J=8.7 Hz, 1H), 4.27 (s, 2H), 4.18 ( q, J=7.5Hz, 2H) , 3.83 (s, 3H) 1.20 (t, J=7.2 Hz, 3H) 325 462.1 * (DMSO, 300MHz), δ 10.30 (s, 1H), 8.02 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.58-7.54(m, 4H), 7.51-7.49 (m, 2H), 7.04 (d, J=8.4 Hz, IH), 6.92 (dd, J=8.7 Hzand 1.8 Hz, 1H), 6.11 (s, 2H), 4.22 (q, J=7.5 Hz, 2H), 3.83 (s, 3H),1.21 (t, J=6.9 Hz, 3H) 326 137-138 396.1 * 327 154-155 386.1 * (DMSO,300 MHz), δ 10.45 (s, 1H), 8.02 (s, 1H), 7.95 (d, J=8.1 Hz, 2H), 7.55(q, J=7.8 Hz, 2H), 7.33 (q, J=3.6 Hz, 2H), 7.25 (s, 1H), 6.95 (dd, J=3.6and J=2.4 Hz, 1H), 6.70 (q, J=1.8 Hz, 1H), 4.22 ( q, J=7.5 Hz, 2H) ,3.84 (s, 3H), 1.22 (t, J=6.9 Hz, 3H) 328 174-175 401.1 * (CDCl₃, 300MHz), δ 8.68 (s, 1H), 8.00 (s, 1H), 7.65 (m, 2H), 7.55 (t, J=8.4 Hz,1H), 7.40 (d, J=7.2 Hz, 1H), 6.95 (dd, J=7.2 and 1.8 Hz, 1H), 6.90 (d,J=2.1, 1H), 6.54 (s, 1H), 4.20 ( q, J=7.2 Hz, 2H) , 3.92 (s, 3H), 2.53(s, 3H), 1.39 (t, J=7.2Hz, 3H) 329 175-176 334.0 * (CDCl₃, 300 MHz), δ7.79 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.49 (t,J=7.8 Hz, 1H), 7.38 (s, 1H), 7.30 (d, J=4.5 Hz, 1H), 6.99 (d, J=2.1 Hz,1H), 6.92 (d, J=2.1 Hz, 1H) 4.19 (q, J=6.9 Hz, 2H), 3.91 (s, 3H), 2.22(s, 3H), 1.39 (t, J=7.2 Hz, 3H) 330 237-238 438.1 * (DMSO, 300 MHz), δ10.90 (s, 1H), 8.71 (s, 1H), 8.18 (d, J=9.9 Hz, IH), 8.06 (s, 1H), 7.97(t, J=9.3 Hz, 2H), 7.63 (t, J=8.1 Hz, 1H), 7.53 (d, J=8.7, 1H), 7.39 (d,J=8.4 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 6.94 (dd, J=8.7 Hz and 2.1 Hz,1H), 4.23 ( q, J=6.6 Hz, 2H) , 3.84 (s, 3H), 1.23 (t, J=7.2 Hz, 3H) 331160-165. 370.5 ** 332 239-145 334.5 * 333 237-240 384.5 ** 334 242-246348.5 ** 335 87-88 297.5 ** 336 129-132 384.5 * 337 135-137 283.4 * 338125-135 367.5 * [M-H] 339 215-219 362.5 ** 340 243-248 334.2 * 341227-230 348.3 ** 342 258-261 337.3 * ¹H NMR (300 MHz, CDCl₃): δ 8.70(1H, s), 7.79 (1H, d, J=1.8 Hz), 7.73 (1H, dd, J=8.5, 1.8 Hz), 7.07 (1H,d, J=8.5 Hz), 6.95 (2H, d, J=8.8 Hz), 6.65 (2H, d, J=8.8 Hz), 3.97 (2H,q, J=7.0 Hz), 3.54 (3H, s), 1.12 (3H, t, J=7.0 Hz). 343 131-133 373.5 *344 177-178 356.5 ** 345 191-192 370.5 ** 346 178-180 384.3 *** 347146-148 357.3 * 348 126-128 267.2 * 349 392.3 *** 350 374.3 ** 351 390.3** 352 388.3 ** 353 350.2 *** 354 388.3 ** 355 384.2 * 356 404.3 * [M-H]357 392.3 * 358 374.3 * 359 390.3 * 360 388.3 * 361 404.3 * 362 609.5 **[M-H] 363 201-207 394.2 ** [M-H] 364 183-188 398.2 ** 365 oil 408.2 ***366 223-225 420.2 *** 367 225-227 434.2 ** 368 168-170 434.2 ** 369174-177 470.2 ** 370 159-164 432.2 * 371 168-170 340.2 * ¹H NMR (300MHz, DMSO- d₆): δ 10.24 (1H, s), 7.75-7.60 (1H, m), 7.60 (2H, d, J=8.8Hz), 7.45- 7.25 (3H, m), 7.41 (2H, d, J=8.8 Hz), 4.21 (2H, q, J=7.0 Hz),3.13 (3H, s), 1.22 (3H, t, J=7.0 Hz). 372 211-212 334.3 ** ¹H NMR (300MHz, DMSO-d₆): δ 9.98 (1H, s), 7.73-7.62 (2H, m), 7.69 (2H, d, J = 8.4Hz), 7.54 (2H, d, J=8.4 Hz), 7.39-7.24 (2H, m), 4.26-4.12 (4H, m), 1.26(3H, t, J=7.0 Hz), 1.20 (3H, t, J=7.3 Hz). 373 222-228 354.2 * [M-H] 374180-186 396.2 * [M-H] 375 161-166 425.6 * [M-H] 376 278.4 * 377 153-156403.1 * ¹H NMR (DMSO, 300 MHz), δ7.66-7.51 (m, 5H), 7.25 (d, J=2.1 Hz,1H), 6.91 (dd, J=8.7 Hz and 2.4 Hz, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.83(s, 3H), 3.65-3.55 (m, 2H), 2.73-2.68 (m, 4H), 1.71-1.54 (m, 4H), 1.18(t, J=7.2 Hz, 3H). 378 376.7 * ¹H NMR (DMSO, 300 MHz), δ 8.84 (t, J=1.8Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.67 (d, J=7.8 Hz, 2H), 7.49 (d, J=8.7Hz, 1H), 7.38 (s, 1H), 7.22 (s, 1H), 7.02 (s, 1H), 6.89 (d, J=7.2 Hz,1H), 4.17 (q, J=6.9 Hz, 2H), 3.80-3.77 (m, 5H), 1.12 (t, J=7.2 Hz, 3H).379 228-232 472.2 ** ¹H NMR (DMSO, 300 MHz), δ7.72-7.67 (m, 2H),7.78-7.68 (m, 2H), 7.55 (d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.97 (dd, J=26.6 Hz and 1.5Hz, 1H), 4.20 (q. J=7.5 Hz, 2H), 3.83 (s, 3H), 3.06 (t,J=4.2 Hz, 6H), 2.76-2.69 (m, 6H), 2.50 (s, 6H), 1.96 (br, 2H), 1.18 (t,J=7.2 Hz, 3H). 380 * ¹H NMR (DMSO, 300 MHz), δ 10.67 (s, 1H), 8.16 (d,J=2.4 Hz, 1H), 8.11 (d, J=4.5 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.73 (d,J=2.4 Hz, 1H), 7.61 (d, J=9.0 Hz, 1H), 7.54 (d, J=9.0 Hz, 1H), 7.27 (s,1H), 6.94 (d, J=8.7 Hz, 1H), 4.28-4.26 (m, 2H), 3.84 (s, 3H), 1.17 (t,J=7.2 Hz, 3H). 381 216-220 410.1 * ¹H NMR (DMSO, 300 MHz), δ 10.34 (s,1H), 8.10 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.1 Hz, 2H), 7.65 (d, J=8.4 Hz,2H), 7.53 (d, J=8.7 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J=8.1 Hz, 2H), 6.94(dd, J=8.7 Hz and 2.4 Hz, 1H), 4.21 (q, J=6.9 Hz, 2H), 3.83 (s, 3H),2.25 (s, 3H), 1.17 (t, J=6.9 Hz, 3H). 382 236-238 ** ¹H NMR (DMSO, 300MHz), δ 10.55 (s, 1H), 8.10 (d, J=7.8 Hz, 2H), 7.83-7.76 (m, 4H), 7.54(d, J=8.4 Hz, 1H), 7.41 (d, J=8.1 Hz, 2H), 7.27 (s, 1H), 6.93 (dd, J=9.9Hz and 1.2 Hz, 1H), 4.22 (q, J=6.9 Hz, 2H), 3.84 (s, 3H), 1.17 (t, J=7.2Hz, 3H). 383 161.2-162.2 362.1 * ¹H NMR (CDCl₃, 300MHz), δ 7.79 (s, 1H),7.65-7.59 (m, 2H), 7.48 (t, J=7.8 Hz, 1H), 7.30 (t, J=11.4 Hz, 2H), 6.96(dd, J=8.7 Hz and 2.1 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H), 4.18 (q, J=7.2Hz, 2H), 3.91 (s, 3H), 2.57-2.52 (m, 1H), 1.36 (t, J=7.2 Hz, 3H)1.28-1.23 (m, 6H). 384 199-201 348.0 * ¹H NMR (CDCl₃, 300 MHz), δ 7.93(d, J=8.4 Hz, 2H), 7.67-7.61 (m, 3H), 6.98 (dd, J=8.7 Hz and 2.1 Hz,1H), 6.88 (d, J=2.1 Hz, 1H), 6.14 (br, 1H), 4.14 (q, J=7.5 Hz, 2H), 3.93(s, 3H), 3.57-3.53 (m, 2H), 1.36-1.26 (m, 6H). 385 213-213.9 362.0 ** ¹HNMR (DMSO, 300 MHz), δ 8.37 (d, J=6.6 Hz, 1H), 7.98 (d, J=7.8 Hz, 2H),7.65 (d, J=7.8 Hz, 2H), 7.50 (d, J=9.0 Hz, 1H), 7.23 (s, 1H), 6.90 (d,J=7.8 Hz, 1H), 4.19-4.16 (m, 2H), 4.08- 4.06 (m, 1H), 3.80 (s, 3H),1.14-1.12 (m, 9H). 386 198-199 359.9 * ¹H NMR (DMSO, 300 MHz), δ 8.59(d, J=4.2 Hz, 1H), 7.97 (d, J=8.1 Hz, 2H), 7.67 (d, J=8.1 Hz, 2H), 7.52(d, J=8.7 Hz, 1H), 7.25 (d, J=2.1 Hz, 1H), 6.92 (dd, J=8.7 Hz and 2.1Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 2.90- 2.80 (m, 1H), 1.16(t, J=7.2 Hz, 3H), 0.69 (q, J=4.8 Hz, 2H), 0.57 (q, J=3.3 Hz, 2H). 387189-189.5 360.1 * ¹H NMR (DMSO, 300 MHz), δ 7.81 (d, J=8.4 Hz, 2H), 7.67(d, J=8.1 Hz, 2H), 7.53 (d, J=8.7 Hz, 1H), 7.25 (d, J=1.8 Hz, 1H), 6.93(dd, J=8.7 Hz and 2.1 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 4.18 (q, J=7.2Hz, 2H), 4.06 (t, J=6.8 Hz, 2H), 3.83 (s, 3H), 2.24 (m, 2H), 1.16 (t,J=7.2 Hz, 3H). 388 160.1-161.8 363.9 * ¹H NMR (DMSO, 300 MHz), δ 8.60(t, J=2.1 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.53(d, J=9.0 Hz, 1H), 7.25 (s, 1H), 6.93 (dd, J=6.9 Hz and 1.8 Hz, 1H),4.72 (t, J=5.4 Hz, 1H), 4.19 (q, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.48 (q,J=6.0 Hz, 2H), 3.33 (m, 2H), 1.15 (t, J=7.2 Hz, 3H). 389 130-132 447.1 *¹H NMR (CDCl₃, 300 MHz), δ 8.36 (br, 1H), 8.12 (d, J=7.2 Hz, 2H),7.67-7.59 (m, 3H), 6.97 (dd, J=9.3 Hz and 1.8 Hz, 1H), 6.89 (s, 1H),4.18 (q, J=7.5 Hz, 2H), 3.98 (br, 2H), 3.84 (s, 3H), 3.67 (q, J=6.9Hz,2H), 2.87 (br, 4H), 2.17 (s, 1H) 2.14 (br, 1H), 2.09 (s, 1H), 1.40 (t,J=10.5Hz, 3H), 1.31 (t, J=7.5 Hz, 3H). 390 236-236.8 396.1 * ¹H NMR(DMSO, 300 MHz), δ 10.42 (s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.79-7.75 (m,4H), 7.55 (d, J=8.7 Hz, 1H), 7.35 (t, J=10.6 Hz, 2H), 7.27 (d, J=2.1 Hz,1H), 7.09 (t, J=10.6 Hz, 1H), 6.94 (dd, J=8.7Hz and 2.1 Hz, 1H), 4.23(m, 2H), 3.84 (s, 3H), 1.18 (t, J=6.9 Hz, 3H). 391 240-242 ** ¹H NMR(DMSO, 300 MHz),δ 10.55 (s, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.82 (m, 4H),7.55 (d, J=8.7 Hz, 1H), 7.41 (d, J=9.0 Hz, 2H), 7.27 (d, J=1.8 Hz, 1H),6.94 (dd, J=8.7 Hz and 2.1 Hz, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.84 (s,3H), 1.78 (t, J=7.1 Hz, 3H). 392 243-246 456.1 * ¹H NMR (DMSO, 300 MHz),δ 10.27 (s, 1H), 8.11 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.54(d, J=8.7 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.29(s, 1H), 6.96-6.91 (m, 2H), 4.25 (q, J=8.5 Hz, 2H), 3.84 (s, 3H), 3.73(s, 3H), 3.72 (s, 3H), 1.18 (t, J=7.2 Hz, 3H). 393 202-206 296.4 ** 394192-195 372.3 *** [M-H] 395 397.4 ** 396 377.2 *** *** 397 377.5 *** ***398 391.5 *** 399 375.5 *** 400 411.3 ** 401 363.3 *** *** 402 439.5 **403 453.5 ** 404 425.5 * 405 425.5 ** 406 503.5 *** 407 483.5 ** 408231-235 358.1 ** 409 163-164 398.3 ** 410 139-141 359.2 ** 411 148-149373.3 ** 412 143-144 373.3 * 413 184-185 370.4 *** 414 156-157 384.4 **415 163-165 384.4 *** 416 173-175 398.4 *** 417 199-201 398.4 *** 418183-184 412.4 *** 419 213-215 398.4 ** 420 241-243 372.5 ** 421 214-216406.3 * 422 259-261 386.5 ** 423 291-294 434.4 * 424 150-153 443.5 * 425273-275 398.4 ** 426 178-180 327.2 ** 427 199-202 330.3 ** 428 144-146319.2 ** [M-H] * 429 200-206 314.3 ** 430 180-186 372.4 ** [M-H] * 431167-173 296.4 * 432 160-162 318.1 * (DMSO, 300 MHz), δ 8.64 (t, J=5.4Hz, 1H), 8.02 (d, J=8.1 Hz, 2H), 7.80-7.65 (m, 4H), 7.40-7.28 (m, 2H),4.21 (q, J=6.9 Hz, 2H), 3.29 (q, J=7.2 Hz, 2H), 1.20-1.08 (m, 6H). 433187-189 329.9 * (DMSO, 300 MHz), δ 8.61 (d, J=3.6 Hz, 1H), 7.79 (d,J=8.1 Hz, 2H), 7.76-7.64 (m, 4H), 7.40-7.27 (m, 2H), 4.20 (q, J=7.2 Hz,2H), 2.88-2.82 (m, 1H), 1.17 (t, J=7.2 Hz, 3H), 0.69 (q, J=7.2 Hz, 2H),0.56 (q, J=7.8 Hz, 2H). 434 170-175 368.4 * 435 112-117 382.5 * 436196-202 280.5 * 437 220-227 342.3 * [M-H] 438 188-194 356.3 * [M-H] 439181-186 358.4 ** 440 177-181 370.3 ** [M-H] 441 459.5 ** 442 397.5 * 443411.5 * 444 439.5 * 445 453.5 ** 446 503.5 * 447 426.5 *** 448 301-303436.5 * ¹H NMR (300 MHz, DMSO-d₆): δ 10.65 (1H, s), 7.94 (1H, s), 7.76(1H, s), 7.48 (1H, d, J=8.5 Hz), 7.45 (2H, d, J=8.5 Hz), 7.33(2H, d,J=8.5 Hz), 7.21 (1H, d, J=2.0 Hz), 6.90 (1H, dd, J=8.5, 2.0 Hz), (3H,s), 4.13 (2H, q, J=7.0 Hz), 3.82 (3H, s), 3.66 (3H, s), 1.15 (3H, t,J=7.0 Hz). 449 242-243 518.5 * ¹H NMR (300 MHz, DMSO-d₆): δ 10.59 (1H,s), 8.49 (1H, d, J=2.3 Hz), 7.81 (1H, dd, J=9.1, 2.3 Hz), 7.52-7.44 (3H,m), 7.29 (2H, d, J=8.5 Hz), 7.21 (1H, d, J=2.3 Hz), 6.90 (2H, d, J=8.8Hz), 4.12 (2H, q, J=7.0 Hz), 3.82 (3H, s), 3.63-3.55 (8H, m), 1.12 (3H,t, J=7.0 Hz). 450 217-220 402.5 ** 451 179-182 438.4 * ¹H NMR (300 MHz,DMSO-d₆): δ 10.87 (1H, s), 7.94 (1H, dt, J=5.0, 1.0 Hz), 7.66 (1H, dt,J=3.5, 1.2 Hz), 7.55-7.48 (3H, m), 7.33 (2H, d, J=8.0 Hz), 7.22 (1H, d,J=1.8 Hz), 7.14 (1H, ddd, J=5.0, 3.8, 1.0 Hz), 6.90 (1H, dt, J=8.8, 1.0Hz), 4.13 (2H, q, J=7.3 Hz), 3.83 (3H, s), 1.13 (3H, t, J = 7.3 Hz). 452299-301 483.4 * ¹H NMR (300 MHz, DMSO-d₆): δ 10.62 (1H, s), 9.12 (1H,dd, J=4.1, 1.7 Hz), 8.53-8.45 (2H, m), 8.29 (1H, d, J=8.5 Hz), 7.78-7.68(2H, m), 7.44 (1H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8 Hz), 7.27 (2H,d,J=8.8 Hz), 7.16 (1H, d, J=2.0 Hz), 6.87 (1H, dd, J=8.8, 2.0 Hz), 4.04(2H, q, J=7.0 Hz), 3.80 (3H, s), 1.06 (3H, t, J=7.0 Hz). 453 198-200416.5 ** 454 180-182 412.4 * ¹H NMR (300 MHz, CDCl₃): δ7.44-7.11 (4.8H,m), 6.97 (1.2H, d, J=8.4 Hz), 6.78-6.69 (2H, m), 4.00-3.90 (2H, m),3.713 (1.2H, s), 3.707 (1.8H, s), 2.93 (1H, v br), 2.12 (1.8H, s), 2.09(1.2H, s), 1.17 (1.2H, t, J=7.3 Hz), 1.14 (1.8H, t, J=7.3 Hz). 455221-223 414.4 * 456 157-159 357.5 ** 457 156-158 464.5 ** 458 272-273496.5 * ¹H NMR (300 MHz, DMSO-d₆): δ 10.10 (1H, s), 8.62 (1H, d, J=8.2Hz), 8.49-8.45 (2H, m), 8.27 (2H, d, J=8.8 Hz), 7.90 (2H, d, J=3.8 Hz),7.72 (2H, d, J=8.8 Hz), 7.70-7.62 (1H, m), 7.55-7.49 (4H, m), 7.26 (1H,d, J = 2.0 Hz), 6.94 (1H, dd, J=8.8, 2.0 Hz), 4.27 (2H, q, J=7.0 Hz),3.85 (3H, s), 1.24 (3H, t, J=7.0 Hz). 459 158-163 368.5 ** 460 oil 368.3** [M-H] 461 200-205 432.3 *** 462 135-140 444.2 *** [M-H] 463 178-179359.5 * 464 164-166 401.5 * 465 99-100 401.5 * 466 164-166 385.5 ** 467169-170 399.5 ** 468 201-202 398.5 ** *** 469 243-245 384.5 ** 470178-180 426.5 *** 471 154-156 412.2 *** 472 215-217 410.5 *** 473189-191 424.5 *** 474 218-222 293.5 * 475 178-181 293.5 *** 476 175-178340.4 ** 477 194-195 418.4 *** 478 172-175 469.5 *** 479 190-192 467.5 *480 207-208 485.4 *** 481 209-211 482.5 * 482 128-130 471.5 ** 483149-150 292.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.32-7.25 (2H, m), 7.19 (1H,d, J=2.4 Hz), 6.97 (1H, dd, J=8.9, 2.4 Hz), 6.92-6.80 (3H, m), 4.17 (2H,q, J=7.3 Hz), 3.89 (3H, s), 3.80 (2H, v br), 1.34 (3H, t, J=7.3 Hz). 484156-157 334.2 * ¹H NMR (300 MHz, CDCl₃): δ 8.16 (1H, d, J=8.5 Hz), 8.00(1H, d, J=8.7 Hz), 7.68 (1H, d, J=8.8 Hz), 7.60-7.50 (2H, m), 7.25 (1H,obscurred), 7.10 (1H, d, J=8.8 Hz), 5.20 (2H, q, J=7.3 Hz), 4.02 (3H,s), 1.55 (3H, t, J=7.3 Hz). 485 128-133 440.2 * 486 116-123 454.2 ** 487175-179 446.2 ** 488 158-164 460.2 *** 489 418.5 ** 490 404.5 ** 491445.2 * 492 463.2 ** 493 477.2 *** 494 336.2 * 495 126-128 444.3 ** 496236-239 ** 497 235-239 * 498 192-194 427.5 ** 499 235-250 *** 500468.2 * 501 420.2 * 502 406.2 * 503 406.2 * 504 412.2 * 505 164-166384.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.52 (1H, t, J=7.9 Hz), 7.47 (1H, t,J=1.9 Hz), 7.36-7.30 (3H, m), 7.18 (1H, d, J=2.3 Hz), 7.00 (1H, dd,J=8.9, 2.3 Hz), 6.91 (1H, br s), 4.18 (2H, q, J=7.3 Hz), 3.90 (3H, s),3.25 (2H, q, J=7.3 Hz), 1.43 (3H, t, J=7.3 Hz), 1.38 (3H, t, J=7.3 Hz)506 156-157 364.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.67 (1H, s), 7.48-7.44(2H, m), 7.33 (1H, d, J=9.0 Hz), 7.26-7.23 (1H, m), 7.19 (1H, d, J=2.3Hz), 6.98 (1H, dd, J=9.0, 2.3 Hz), 6.79 (1H, s), 4.24 (2H, q, J=7.3 Hz),4.19 (2H, q, J=7.3 Hz), 1.36 (3H, t, J=7.3 Hz), 1.32 (3H, t, J=7.3 Hz).507 152-153 378.2 * ¹H NMR (300 MHz, CDCl₃): δ 7.66 (1H, s), 7.46 (2H,d, J=5.0 Hz), 7.33 (1H, d, J=9.0 Hz), 7.26-7.21 (1H, m), 7.19 (1H, d,J=2.3 Hz), 6.98 (1H, dd, J=9.0, 2.3 Hz), 6.72 (1H, s), 5.03 (1H, hp, H =6.1 Hz), 4.19 (2H, q, J=7.3 Hz), 3.89 (3H, s), 1.36 (3H, t, J=7.3 Hz),1.30 (6H, d, J=6.1 Hz). 508 glass 378.2 * ¹H NMR (300 MHz, CDCl₃): δ7.67 (1H, s), 7.48-7.45 (2H, m), 7.33 (1H, d, J=9.0 Hz), 7.27-7.23 (1H,m), 7.19 (1H, d, J=2.3 Hz), 6.98 (1H, dd, J=9.0, 2.3 Hz), 6.77 (1H, s),4.19 (2H, q, J=7.0 Hz), 4.14 (2H, t, J=6.7 Hz), 3.89 (3H, s), 1.72 (2H,m, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz), 0.99 (3H, t, J=6.5 Hz). 509 92-95412.1 * ¹H NMR (300 MHz, CDCl₃): δ 7.67 (1H, s), 7.48-7.45 (2H, m), 7.33(1H, d, J=8.8 Hz), 7.27-7.24 (1H, m), 7.19 (1H, d, J=2.3 Hz), 6.99 (1H,dd, J=8.8, 2.3 Hz), 6.83 (1H, s), 4.35 (2H, t, J=6.0 Hz), 4.19 (2H, q,J=7.3 Hz), 3.89 (3H, s), 3.66 (2H, t, J=6.5 Hz), 2.16 (2H, p, J=6.1 Hz),1.37 (3H, t, J=7.3 Hz). 510 210-211 368.3 ** ¹H NMR (300 MHz, 9:1 CDCl₃-DMSO-d₆): δ 9.64 (1H, s), 7.28-7.17 (3H, m), 7.14 (1H, d, J=9.0 Hz),7.04 (1H, d, J=7.3 Hz), 6.91 (1H, d, J=2.0 Hz), 6.75 (1H, dd, J=9.0, 2.0Hz), 3.95 (2H, q, J=7.3 Hz), 3.66 (3H, s), 2.81 (3H, s), 1.15 (3H, t,J=7.3 Hz). 511 146-148 377.3 * ¹H NMR (300 MHz, CDCl₃): δ 7.34-7.27 (2H,m), 7.19 (1H, d, J=2.3 Hz), 6.97 (1H, dd, J=8.8, 2.3 Hz), 6.88-6.79 (3H,m), 4.17 (2H, q, J=7.0 Hz), 3.89 (3H, s), 3.87 (2H, v br), 1.34 (3H, t,J=7.0 Hz). 512 67-69 407.2 * ¹H NMR (300 MHz, CDCl₃): δ 10.06 (1H, s),7.86 (1H, s), 7.56-7.47 (2H, m), 7.36-7.30 (3H, m), 7.19 (1H, d, J=2.0Hz), 7.00-6.96 (1H, m), 4.62 (1H, br), 4.27 (2H, q, J=7.0 Hz), 4.18 (2H,q, J=7.0 Hz), 3.89 (3H, s), 1.37 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0Hz). 513 210-211 479.2 * ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 8.44(2H, d, J=7.0 Hz), 7.61 (1H, s), 7.45 (1H, s), 7.36- 7.13 (3H, m), 7.10(2H, d, J=8.8 Hz), 6.93 (1H, d, J=7.6 Hz), 6.89 (1H, d, J=7.9 Hz), 6.85(1H, d, J=2.3 Hz), 6.69 (1H, dd, J=8.8, 2.3 Hz), 3.94 (2H, q, J = 7.0Hz), 3.60 (3H, s), 1.08 (3H, t, J=7.0 Hz). ¹⁹F NMR (300 MHz, 9:1CDCl₃-DMSO- d₆): δ −63.02 (3F, s). 514 248-250 268.2 * 515 137-139 381.1** 516 155-156 395.3 ** . ¹H NMR (300 MHz, CDCl₃): δ 7.57 (1H, d, J=8.5Hz), 7.45 (2H, d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.25 (1H, s), 6.95(1H, dd, J=9.1, 1.7 Hz), 6.67 (1H, s), 6.54 (1H, t, J=74.8 Hz), 6.48(1H, s), 4.15 (2H, q), 3.23 (2H, q), 1.45 (3H, t, J=7.5 Hz), 1.32 (3H,t, J=7.2 Hz). 517 160-161 409.1 * 518 197-199 392.1 ** 519 174-175 406.1*** 520 175-177 420.0 *** ¹H NMR (300 MHz, CDCl₃): δ 7.73 (1H, d, J=8.4Hz), 7.52 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=8.2 Hz), 7.25 (1H, s), 7.13(1H, dd, J=7.5, 2.4 Hz), 6.96 (1H, s), 6.56 (1H, t, J=74.1 Hz), 4.16(2H, q), 3.26 (2H, q), 1.46 (3H, t, J=7.5 Hz), 1.32 (3H, t, J=6.9 Hz).521 184-186 [NH-] *** 418.1 522 187-188 [NH-] 432.1 *** 523 190-192[NH-] *** 418.1 524 186-188 434.2 *** 525 458.2 ** 526 490.3 *** 527493.3 ** 528 475.3 ** 529 459.2 ** 530 461.3 *** 531 479.5 ** 532 458.2** 533 490.3 ** 534 493.3 *** 535 475.3 *** 536 459.2 ** 537 461.3 ***538 459.2 ** 539 477.3 *** 540 182-183 385.2 ** 541 149-151 399.2 * 542186-188 413.2 ** 543 197-200 324.2 ** 544 263-265 392.2 *** *** 545203-205 382.2 ** ** 546 208-210 396.2 *** 547 180-182 410.2 *** 548171-174 402.1 ** 549 150-153 416.1 *** 550 183-185 430.0 ** 551 187-190462.3 ** 552 185-188 428.1 *** 553 412.2 * 554 388.2 * 555 408.2 * 556440.2 * 557 454.3 ** [M-H] 558 87-90 406.2 ** 559 92-94 386.2 * 560207-210 434.2 * 561 182-185 398.2 * 562 oil 420.1 *** 563 210-212 436.1** 564 210-211 377.1 ** ¹H NMR (DMSO, 300 MHz), δ 8.61 (t, J=2.4 Hz,1H), 8.35 (br, 2H), 8.04 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.52(d, J=8.7 Hz, 2H), 7.26 (d, J=2.4 Hz, 1H), 6.94 (dd, J=8.7 Hz and 2.1Hz, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.83 (s, 3H), 3.55 (q, J=6.0 Hz, 2H),3.09 (br, 2H), 2.60-2.53 (m, 3H), 1.15(t, J=7.2 Hz, 3H). 565 228-229304.2 * ¹H NMR (DMSO, 300 MHz), δ 10.23 (s, 1H), 7.79 (d, J=8.4 Hz, 2H),7.69 (d, J=7.2 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 17.54 (d, J=7.8 Hz, 2H),7.38-7.22 (m, 2H), 4.20 (q, J=7.2 Hz, 2H), 2.07 (s, 3H), 1.19 (t, J=7.2Hz, 3H). 566 334.1 * ¹H NMR (CDCl₃, 300 MHz), δ 8.42 (s, 1H), 7.80-7.76(m, 3H), 7.54 (d, J=8.4 Hz, 2H), 7.44 (d, J=7.8 Hz, 1H), 7.36-7.26 (m,2H), 4.20 (q, J=7.2 Hz, 2H), 4.07 (s, 2H), 3.55 (s, 3H), 1.36 (t, J=7.2Hz, 3H). 567 238.2-238.6 344.2 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.78- 7.73(m, 2H), 7.60 (d, J=5.7 Hz, 2H), 7.51 (d, J=5.7 Hz, 1H), 7.38-7.28 (m,2H), 4.20 (q, J=6.8 Hz, 2H), 3.26 (br, 1H), 2.43 (br, 2H), 2.27 (br,2H), 2.06- 1.90 (m, 2H), 1.36 (t, J=6.9 Hz, 3H). 568 195-200 320.0 * ¹HNMR (CDCl₃, 400 MHz), δ 7.99 (d, J=8.4 Hz, 2H), 7.66 (d, J=7.6 Hz, 2H),7.35 (d, J=9.2 Hz, 1H), 7.20 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.15 (br,1H), 5.65 (br, 1H), 4.17 (q, J=6.8 Hz, 2H), 3.90 (s, 3H), 1.36 (t, J=7.6Hz, 3H). 569 348.1 ** ¹H NMR (CDCl₃, 400 MHz), δ 7.93 (d, J=8.4 Hz, 2H),7.62 (d, J=8.0 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H),7.01 (dd, J=8.8 Hz and J=2.4 Hz, 1H), 6.19 (br, 1H), 4.16 (q, J=7.2 Hz,2H), 3.90 (s, 3H), 3.56-3.52 (m, 2H), 1.38-1.23 (m, 6H). 570 220-222362.1 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.92 (d, J=8.1 Hz, 2H), 7.62 (d,J=8.1 Hz, 2H), 7.34 (d, J=9.0 Hz, 111), 7.19 (d, J=2.1 Hz, 1H), 7.00(dd, J=9.0 Hz and 2.4 Hz, 1H), 6.02 (d, J=7.8 Hz, 1H), 4.35 (m, 1H),4.16 (q, J=7.2 Hz, 2H), 3.90 (s, 3H), 1.36-1.26 (m, 9H). 571 360.0 ** ¹HNMR (CDCl₃, 400 MHz), δ 7.91 (d, J=8.0 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H),7.34 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 7.01 (dd, J=9.2 Hz and2.4 Hz, 1H), 6.34 (s, 1H), 4.15 (q, J=7.2 Hz, 2H), 3.90 (s, 3H),2.97-2.93 (m, 1H), 1.34 (t, J=7.2 Hz, 3H), 0.66 (q, J=7.2 Hz, 2H), 0.07(t, J=2.1 Hz, 2H). 572 168-171 378.0 ** ¹H NMR (CDCl₃, 300 MHz), δ 7.96(d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.19(d, J=2.1 Hz, IH), 7.02 (dd, J=8.4 Hz and 2.4 Hz, 1H), 6.60 (br, 1H),4.16 (q, J=6.6 Hz, 2H), 3.90 (s, 3H), 3.68 (q, J=4.5 Hz, 2H), 3.59 (t,J=4.8 Hz, 2H), 3.41 (s, 3H), 1.35 (t, J=6.9 Hz, 3H). 573 417.2 * ¹H NMR(CDCl₃, 400 MHz), δ 7.59 (s, 4H), 7.34 (d, J=8.8 Hz, 1H), 7.20 (s, 1H),7.01 (d, J=8.4 Hz, 1H), 4.15 (q, J=6.4 Hz, 2H), 3.90 (s, 3H), 3.90-3.79(m, 2H), 3.60 (br, 1H), 3.54 (q, J=5.6 Hz, 1H), 2.78 (br, 1H), 2.69-2.67(m, 1H), 2.61 (br, 2H), 2.41 (d, J=18.4 Hz, 3H), 2.04 (br, 1H), 1.92(br, 1H), 1.34 (t, J=6.8 Hz, 3H). 574 155-161 427.4 * 575 144-146 345.2** 576 141-142 425.4 * 577 171-173 345.4 ** 578 171-173 317.4 ** 579178-179 368.5 ** [M-H] 580 198-200 370.4 *** 581 378.5 ** 582 392.5 **583 410.4 ** 584 426.4 * 585 406.5 ** 586 440.4 ** 587 406.5 ** 588402.5 * 589 422.5 ** 590 446.5 ** 591 420.5 * 592 416.4 * 593 454.5 *594 412.4 * 595 420.5 * 596 404.4 ** 597 418.5 * 598 169-170 382.5 * ¹HNMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J=8.8 Hz), 7.53 (1H, t, J=7.9 Hz),7.46 (1H, t, J=1.9 Hz), 7.34- 7.29 (2H, m), 6.97 (1H, dd, J=8.8, 2.3Hz), 6.95 (1H, s), 6.86 (1H, d, J=2.3 Hz), 4.08 (2H, t, J=7.6 Hz), 3.91(3H, s), 3.13 (3H, s), 1.75 (2H, hx, J=6.6 Hz), 0.80 (3H, t, J=7.3 Hz).599 163-164 398.4 * ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J=8.8 Hz),7.51 (1H, dd, J=8.5, 7.3 Hz), 7.44 (1H, t, J=1.8 Hz), 7.30 (2H, dd,J=7.9, 2.0 Hz), 6.97 (1H, dd, J=8.8, 2.3 Hz), 6.86 (1H, d, J=2.3 Hz),6.85 (1H, s), 4.08 (2H, t, J=7.6 Hz), 3.91 (3H, s), 3.25 (2H, q, J=7.3Hz), 1.75 (2H, hx, J=7.6 Hz), 1.42 (3H, t, J=7.5 Hz), 0.80 (3H, t, J=7.4Hz). 600 144-145 391.5 * ¹H NMR (300 MHz, CDCl₃): δ 7.60 (1H, d, J=8.8Hz), 7.57-7.54 (1H, m), 7.35-7.31 (2H, m), 7.13-7.09 (1H, m), 6.94 (1H,dd, J=8.8, 2.0 Hz), 6.84 (1H, d, J=2.0 Hz), 4.07 (2H, t, J=7.4 Hz), 3.89(3H, s), 3.21 (2H, t, J=7.0 Hz), 1.68 (2H, hx, J=7.3 Hz), 1.53 (2H, hx,J=7.3 Hz), 0.91 (3H, t, J=7.3 Hz), 0.73 (3H, t, J=7.4 Hz). 601 195-200400.4 *** [M-H] 602 179-184 398.4 *** [M-H] 603 422.4 * 604 410.3 * 605175-180 419.4 * 606 166-170 433.4 *** 607 189-194 449.5 *** 608 223-228452.9 ** 609 230-234 439.4 ** 610 226-231 424.8 ** 611 126-128 396.4 **612 198-200 410.4 ** 613 198-200 [NH-] *** 430.4 614 176-177 [NH-] ***444.4 615 220-225 440.3 * [M-H] 616 143-149 414.4 *** [M-H] 617 164-167433.8 *** [M-H] 618 205-211 368.4 *** 619 201-206 382.3 ** 620 215-223367.4 ** 621 187-188 412.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d,J=8.8 Hz), 7.50 (2H, d, J=8.5 Hz), 7.36 (2H, d, J=8.5 Hz), 6.97 (1H, dd,J=8.8, 2.3 Hz), 6.86 (1H, d, J=2.3 Hz), 6.79 (1H, s), 4.05 (2H, t, J=7.6Hz), 3.91 (3H, s), 3.23-3.17 (2H, m), 1.93 (2H, hx, J = 7.3 Hz), 1.73(2H, hx, J=7.6 Hz), 1.09 (3H, t, J=7.4 Hz), 0.79 (3H, t, J=7.4 Hz). 622182-183 412.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.8 Hz), 7.48(2H, d, J=8.5 Hz), 7.38 (2H, d, J=8.5 Hz), 6.96 (1H, dd, J=8.8, 2.3 Hz),6.86 (1H, d, J=2.3 Hz), 6.83 (1H, s), 4.05 (2H, t, J=7.6 Hz), 3.90 (3H,s), 3.43 (1H, hp, J=6.6 Hz), 1.73 (2H, hx, J=7.6 Hz), 1.46 (6H, d, J=6.6 Hz), 0.79 (3H, t, J = 7.5 Hz). 623 217-218 460.4 ** ¹H NMR (300 MHz,CDCl₃): δ 7.65 (1H, d, J=8.8 Hz), 7.47 (2H, d, J=8.5 Hz), 7.40-7.28 (5H,m), 7.25 (2H, d, J=8.5 Hz), 6.97 (1H, dd, J=8.8, 2.3 Hz), 6.86 (1H, d,J=2.3 Hz), 6.55 (1H, s), 4.45 (2H, s), 4.05 (2H, t, J=7.6 Hz), 3.91 (3H,s), 1.74 (2H, hx, J=7.3 Hz), 0.80 (3H, t, J = 7.4 Hz). 624 187-188 378.5** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.5 Hz), 7.57 (2H, d, J=8.8Hz), 7.46 (2H, d, J=8.8 Hz), 6.95 (1H, dd, J=8.8, 2.3 Hz), 6.85 (1H, d,J=2.3 Hz), 6.79 (1H, s), 4.26 (2H, q, J=7.0 Hz), 4.05 (2H, t, J=7.5 Hz),3.90 (3H, s), 1.72 (2H, hx, J=7.6 Hz), 1.34 (3H, t, J=7.0 Hz), 0.78 (3H,t, J=7.4 Hz). 625 152-153 392.4 *** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H,d, J=8.5 Hz), 7.57 (2H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 6.95 (1H,dd, J=8.5, 2.3 Hz), 6.85 (1H, d, J=2.3 Hz), 6.77 (1H, s), 4.17 (2H, t,J=6.7 Hz), 4.05 (2H, t, J=7.4 Hz), 3.90 (3H, s), 1.73 (2H, hx, J=7.3Hz), 1.00 (3H, t, J=7.4 Hz), 0.78 (3H, t, J=7.4 Hz). 626 193-194 377.5** ¹H NMR (300 MHz, CDCl₃): δ 7.61 (1H, d, J=8.5 Hz), 7.52 (2H, d, J=8.8Hz), 7.41 (2H, d, J=8.8 Hz), 7.30 (1H, br), 6.96 (1H, dd, J=8.8, 2.0Hz), 6.86 (1H, d, J=2.0 Hz), 4.05 (2H, t, J=7.6 Hz), 3.90 (3H, s), 3.32(2H, q, J=7.3 Hz), 1.71 (2H, hx, J=7.3 Hz), 1.19 (3H, t, J=7.3 Hz), 0.77(3H, t, J=7.3 Hz). 627 188-189 391.5 *** ¹H NMR (300 MHz, CDCl₃): δ 7.61(1H, d, J=8.5 Hz), 7.52 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=8.8 Hz), 7.34(1H, br), 6.96 (1H, dd, J=8.5, 2.0 Hz), 6.86 (1H, d, J=2.0 Hz), 4.05(2H, t, J=7.4 Hz), 3.90 (3H, s), 3.24 (2H, t, J=7.0 Hz), 1.72 (2H, hx,J=7.6 Hz), 1.57 (2H, hx, J=7.0 Hz), 0.95 (3H, t, J=7.3 Hz), 0.77 (3H, t,J=7.3 Hz). 628 221-226 381.4 ** 629 204-210 436.3 * 630 205-210 416.3 **631 177-182 428.5 ** [M-H] 632 176-178 366.4 ** [M-H] 633 159-161 380.5** [M-H] 634 163-165 396.3 ** 635 200-201 392.5 *** [M-H] 636 97-89428.4 *** [M-H] 637 398.4 *** 638 390.5 * 639 159-160 412.5 * ¹H NMR(300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.8 Hz), 7.50 (1H, t, J=7.9 Hz), 7.44(1H, t, J=1.8 Hz), 7.33-7.28 (2H, m), 7.18 (1H, s), 6.96 (1H, dd, J=8.8,2.3 Hz), 6.86 (1H, d, J=2.3 Hz), 4.08 (2H, t, J=7.6 Hz), 3.90 (3H, s),3.22-3.16 (2H, m), 1.90 (2H, hx, J=7.8 Hz), 1.74 (2H, hx, J=7.6 Hz),1.05 (3H, t, J=7.4 Hz), 0.79 (3H, t, J=7.5 Hz). 640 197-198 396.5 ** ¹HNMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz),7.48 (2H, d, J=8.8 Hz), 6.95 (1H, dd, J=8.8, 2.0 Hz), 6.92 (1H, s), 6.85(1H, d, J=2.0 Hz), 4.62 (2H, dt, J=74.3, 4.2 Hz), 4.50 (2H, dt, J=55.8,4.2 Hz), 4.05 (2H, t, J=7.6 Hz), 3.90 (3H, s), 1.72 (2H, hx, J = 7.6Hz), 0.78 (3H, t, J=7.4 Hz). ¹⁹F NMR (300 MHz, CDCl₃): δ 5.11 (1F, m).641 177-178 392.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.8 Hz),7.57 (2H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 6.95 (1H, dd, J=8.5, 2.0Hz), 6.85 (1H, d, J=2.0 Hz), 6.72 (1H, s), 5.05 (1H, hp, J=7.1 Hz), 4.05(2H, t, J = 7.6 Hz), 3.90 (3H, s), 1.72 (2H, hx, J=7.6 Hz), 1.33 (6H, d,J= 7.1 Hz), 0.78 (3H, t, J=7.4 Hz). 642 152-153 426.5 ¹H NMR (300 MHz,CDCl₃): δ 7.66-7.57 (3H, m), 7.53 (2H, d, J=8.8 Hz), 6.97 (1H, dd,J=8.8, 2.0 Hz), 6.86 (1H, d, J = 2.0 Hz), 4.07 (2H, t, J=7.4 Hz), 3.91(3H, s), 3.46 (3H,s), 3.40 (1H, hp, J = 7.0 Hz), 1.74 (2H, hx, J = 7.3Hz), 1.40 (6H, d, J=7.0 Hz), 0.79 (3H, t, J =7.4 Hz). 643 150-151 412.4** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J=8.8 Hz), 7.58 (2H, d, J=9.0Hz), 7.53 (2H, d, J = 9.0 Hz), 6.97 (1H, dd, J=8.8, 2.0 Hz), 6.86 (1H,d, J=2.0 Hz), 4.07 (2H, t, J=7.6 Hz), 3.91 (3H, s), 3.44 (3H, s), 3.12(2H, q, J=7.6 Hz), 1.75 (2H, hx, J=7.6 Hz), 1.41 (3H, t, J=7.3 Hz), 0.79(3H, t, J=7.5 Hz). 644 348.2 * (DMSO, 300 MHz), δ 10.12 (s, 1H), 7.77(d, J=8.4 Hz, 2H), 7.58 (d, J=8.7 Hz, 1H), 7.49 (d, J=8.7 Hz, 2H), 7.03(s, IH), 6.92 (d, J=8.4 Hz, 1H), 4.13 (q, J=6.9 Hz, 2H), 3.77 (s, 3H),2.31 (q, J=7.5 Hz, 2H), 1.16 (t, J=8.7 Hz, 3H), 1.06 (t, J=7.5 Hz, 3H).645 242-244 410.2 * (DMSO, 300 MHz), δ 10.33 (s, 1H), 7.99 (d, J=8.4 Hz,2H), 7.72 (d, J=7.8 Hz, 1H), 7.64-7.56 (m, 4H), 7.51 (d, J=1.8 Hz, 1H),7.36-7.07 (m, 2H), 7.06 (d, J=8.1 Hz, IH), 6.12 (s, 2H), 4.22 (q, J=7.2Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). 646 356.2 ** (DMSO, 300 MHz), δ10.47(s, 1H), 8.01-7.96 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.65-7.59 (m, 3H),7.38-7.29 (m, 3H), 6.71 (dd, J=3.9 Hz and J=1.8 Hz, 1H), 4.22 (q, J=6.9Hz, 2H), 1.21 (t, J=7.2 Hz, 3H). 647 430.1 * (DMSO, 300 MHz), δ 10.56(s, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.84-7.76 (m, 4H), 7.67 (d, J=9.0 Hz,IH), 7.41 (d, J=9.0 Hz, 2H), 7.11 (d, J=8.7 Hz, 1H), 6.98 (dd, J=8.7 Hzand 2.1 Hz, 1H), 4.22 (q, J=7.2 Hz, 2H), 3.82 (s, 3H), 1.18 (t, J=7.2Hz, 3H). 648 464.0 ** (DMSO, 300 MHz), δ 10.69 (s, 1H), 8.18-8.09 (m,3H), 7.82-7.72 (m, 3H), 7.70-7.56 (m, 2H), 7.11 (d, J=2.1 Hz, 1H), 6.96(dd, J=8.1 Hz and 2.4 Hz, IH), 4.22 (q, J=7.2 Hz, 2H), 3.82 (s, 3H),1.19 (t, J=7.2 Hz, 3H). 649 210-212 410.5 ** ¹H NMR (300 MHz, DMSO- d₆):δ 7.60 (2H, d, J=8.8 Hz), 7.50 (1H, d, J=8.8 Hz), 7.36 (2H, d, J=8.8Hz), 7.25 (1H, d, J=2.1 Hz), 6.91 (1H, dd, J= 8.8, 2.1 Hz), 4.15 (2H, t,J=7.3 Hz), 3.833 (2H, t, J=6.4 Hz), 3.831 (3H, s), 3.57 (2H, t, J=7.3Hz), 2.45-2.40 (2H, m), 1.54 (2H, hx, J = 7.3 Hz), 0.62 (3H, t, J=7.3Hz). 650 165-166 384.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J=8.8Hz), 7.54 (4H, s), 6.96 (1H, dd, J=8.8, 2.0 Hz), 6.87 (1H, d, J=2.0 Hz),4.84 (1H, br t, J=6.1 Hz), 4.41 (2H, d, J=6.1 Hz), 4.13 (2H, q, J=7.3Hz), 3.90 (3H, s), 2.97 (3H, s), 1.33 (3H, t, J=7.3 Hz). 651 146-147384.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63 (1H, d, J=8.8 Hz), 7.56-7.45(4H, m), 6.96 (1H, dd, J=8.8, 2.0 Hz), 6.87 (1H, d, J=2.0 Hz), 4.89 (1H,br t, J=5.9 Hz), 4.42 (2H, d, J=5.9 Hz), 4.13 (2H, t, J=7.0 Hz), 3.91(3H, s), 2.94 (3H, s), 1.34 (3H, t, J=7.0 Hz). 652 191-194 418.5 *** 653foam 469.5 * 654 197-201 485.5 * 655 184-187 424.2 * 656 159-161 346.2 *657 196-198 388.2 * 658 203-205 400.5 * 659 175-177 458.4 ** 660 215-217394.5 ** 661 156-158 458.5 *** 662 398.4 *** 663 308.3 * 664 424.4 * 665444.5 * 666 207-209 424.4 *** 667 242-244 424.4 *** 668 171-174 483.0 **669 213-215 461.5 *** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.73 (1H,s), 8.76 (1H, s), 8.54 (1H, d, J=5.2 Hz), 8.11 (1H, d, J=7.9 Hz), 7.58(1H, dd, J=7.9, 5.2 Hz), 7.45 (1H, d, J=9.3 Hz), 7.28 (4H, s), 6.88-6.82(2H, m), 5.15 (2H, s), 3.97 (2H, q, J=7.2 Hz), 2.99 (2H, q, J=7.3 Hz),1.21 (3H, t, J=7.3 Hz), 1.15 (3H, t, J=7.2 Hz). 670 231-233 473.4 *** ¹HNMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.59 (1H, s), 8.87 (1H, s), 8.60(1H, d, J=5.2 Hz), 8.35 (1H, d, J=7.6 Hz), 7.80 (1H, dd, J=7.6, 5.2 Hz),7.45 (1H, d, J=8.5 Hz), 7.32-7.23 (4H, m), 6.88 (1H, d, J=2.0 Hz), 6.83(1H, dd, J=8.5, 2.0 Hz), 5.21 (2H, s), 3.97 (2H, q, J=7.3 Hz), 2.44-2.35(1H, m), 1.14 (3H, t, J=7.3 Hz), 1.07-0.99 (2H, m), 0.84-0.78 (2H, m).671 221-222 461.4 *** ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.72 (1H,s), 8.56 (1H, d, J=5.0 Hz), 8.13 (1H, br t, J=7 Hz), 7.87 (1H, d, J=7.6Hz), 7.53- 7.50 (1H, m), 7.41 (1H, d, J=8.5 Hz), 7.25 (4H, s), 7.01 (1H,d, J=2.0 Hz), 6.86 (1H, dd, J=8.5, 2.0 Hz), 5.50 (2H, s), 3.98 (2H, q,J=7.3 Hz), 2.97 (2H, q, J=7.3 Hz), 1.19 (3H, t, J=7.3 Hz), 1.11 (3H, t,J=7.3 Hz). 672 165-166 415.5 *** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d,J=8.8 Hz), 7.55 (4H, s), 6.97 (1H, dd, J=8.8, 2.3 Hz), 6.88 (1H, d,J=2.3 Hz), 4.41 (2H, s), 4.14 (2H, q, J=7.3 Hz), 3.91 (3H, s), 2.91 (3H,s), 2.86 (3H, s), 1.35 (3H, t, J=7.3 Hz). 673 131-132 398.4 * ¹H NMR(300 MHz, CDCl₃): δ 7.65 (1H, d, J=8.8 Hz), 7.57-7.48 (4H, m), 6.97 (1H,dd, J=8.8, 2.0 Hz), 6.88 (1H, d, J=2.0 Hz), 4.42 (2H, s), 4.15 (2H, q,J=7.3 Hz), 3.91 (3H, s), 2.89 (3H, s), 2.87 (3H, s), 1.37 (3H, t, J=7.3Hz). 674 159-160 414.4 * ¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.67(1H, s), 7.36 (1H, d, J=8.8 Hz), 7.31 (2H, d, J=8.8 Hz), 7.23 (2H, d,J=8.8 Hz), 6.76 (1H, d, J =2.0 Hz), 6.72 (1H, dd, J=8.8, 2.0 Hz), 4.05(2H, t, J=5.6 Hz), 3.68 (3H, s), 3.44 (2H, t, J=5.6 Hz), 3.00 (3H, s),2.95 (2H, q, J=7.3 Hz), 1.17 (3H, t, J=7.3 Hz). 675 460.4 ** ¹H NMR (300MHz, 9:1 CDCl₃- DMSO-d₆): δ 9.83 (1H, s), 7.61-7.27 (5H, m), 6.82-6.78(2H, m), 4.10 (2H, t, J=5.6 Hz), 3.74 (3H, s), 3.56-3.47 (4H, m), 3.16(2H, t, J=7.3 Hz), 3.06 (3H, s), 2.21-2.01 (2H, m). 676 174-175 394.4 **¹H NMR (300 MHz, 9:1 CDCl₃- DMSO-d₆): 5 8.77 (1H, s), 7.51 (2H, d, J=8.5Hz), 7.41 (1H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 6.80 (1H, d, J=2.0Hz), 6.77 (1H, dd, J=8.5, 2.0 Hz), 4.12-4.04 (4H, m), 3.72 (3H, s), 3.46(2H, t, J=5.6 Hz), 3.04 (3H, s), 1.18 (3H, t, J=7.2 Hz). 677 133-134408.4 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64- 7.51 (5H, m), 6.98-6.94 (2H,m), 6.78 (1H, s), 4.25 (2H, t, J=5.7 Hz), 4.17 (2H, t, J=6.7 Hz), 3.90(3H, s), 3.63 (2H, t, J=5.7 Hz), 3.22 (3H, s), 1.73 (2H, hx, J=7.3 Hz),1.00 (3H, t, J=7.4 Hz). 678 184-188 318.3 * 679 212-220 389.5 ** 680163-168 403.3 *** 681 192-197 403.3 ** 682 194-195 460.4 ** 683 157-159494.2 ** 684 175-176 412.5 * 685 140-141 448.4 ** 686 173-174 424.5 **687 124-125 420.4 *** 688 178-179 410.4 ** 689 204-205 409.5 ** 690192-193 423.9 ** 691 203-205 383.8 ** 692 175-176 397.8 ** 693 163-164411.8 *** 694 135-136 383.8 ** 695 159-160 397.8 ** 696 194-196 397.8 **697 foam 467.0 *** 698 foam 499.5 ** 699 255-258 427.8 *** 701 188-194395.8 ** 702 147-150 409.8 ** 703 160-165 424.5 ** 704 169-170 433.4 *705 199-201 397.4 * 706 151-153 396.4 *** 707 159-161 412.5 ** 708175-177 426.5 ** 709 166-168 424.4 *** 710 oil 458.5 * 711 oil 424.5 *712 259-261 316.5 * 713 199-202 474.5 ** 714 52-53 281.4 ** 715 174-175424.1 *** 716 204-205 422.4 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 0.04-0.12(m, 2H), 0.41-0.50 (m, 2H), 0.98-1.13 (m, 1H), 2.54-2.67 (m, 2H), 3.45(t, 2H), 3.87 (t, 3H), 3.91 (s, 2H), 3.99 (d, 2H), 6.93-6.99 (m, 2H),7.36- 7.43 (m, 2H), 7.49-7.56 (m, 2H), 7.61- 7.66 (m, 1H). 717 205-207424.5 ** 718 195-196 450.2 ** 719 192-193 410.2 * 720 172-178 410.5 **721 158-160 404.6 ** 722 160-162 432.6 ** 723 175-180 418.6 ** 724168-170 416.4 ** 725 215-216 397.5 ** 726 221-222 411.4 ** 727 217-218487.5 ** 728 197-199 479.5 *** 729 213-217 493.6 * 730 210-214 495.2 ***731 173-174 388.5 *** 732 219-221 378.2 ** 733 146-148 354.5 * 734167-169 412.5 ** 735 123-125 426.5 *** 736 125-126 [NH-] *** 438.5 737153-155 [NH-] ** 438.5 738 149-151 [NH-] *** 442.4 739 oil 456.5 * 740203-205 424.9 ** 741 194-196 438.9 *** 742 171-173 [NH-] ** 451.5 743129-129 465.5 *** 744 92-93 412.5 *** 745 oil 426.5 *** 746 oil 440.5 *747 136-137 410.5 *** 748 186-188 391.6 *** 749 176-178 405.6 *** 750173-174 419.6 *** 751 159-162 405.6 ** 752 198-202 396.5 ** 753 157-161409.9 *** 754 146-150 424.5 ** 755 357.2 *** ¹H NMR (DMSO, 300 MHz),δ11.02 (s, 1H), 8.83 (d, J=1.8 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.71 (d,J=7.2 Hz, 1H), 7.66-7.63 (m, 3H), 7.39-7.26 (m, 3H), 4.22 (q, J=7.5 Hz,2H), 1.20 (t, J=6.9 Hz, 3H). 756 388.0 *** ¹H NMR (CDC1₃, 300 MHz), δ8.04 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.5 Hz, 1H), 7.60 (d,J=8.7 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 7.42-7.31 (m, 2H), 4.23 (t, J=7.8Hz, 2H), 3.01 (s, 3H), 1.38 (t, J=7.2, 3H). 757 218-225 358.2 *** ¹H NMR(CDC1₃, 300 MHz), δ7.79- 7.76 (m, 3H), 7.58 (d, J=8.4 Hz, 2H), 7.46 (d,J=7.5 Hz, 2H), 7.39-7.32 (m, 2H), 4.23 (q, J=7.5 Hz, 2H), 2.71 (s, 3H),2.54 (s, 3H), 1.38 (t, J=7.2 Hz, 3 H). 758 149-153 320.2 *** 759 376.2*** ¹H NMR (DMSO, 300 MHz) δ 10.14 (s, 1H), 7.79 (d, J=8.4 Hz, 2H),7.58-7.45 (m, 3H), 7.22 (d, J=1.5 Hz, 1H), 6.88 (dd, J=8.7 Hz and 1.8Hz, 1H), 4.75-4.67 (m, 1H), 4.15 (q, J=6.9 Hz, 2H), 2.34 (q, J=7.6 Hz,2H), 1.27 (d, J=6.0 Hz, 6H), 1.16-1.07 (m, 6H). 760 402.2 *** (DMSO, 300MHz) δ9.99 (s, 1H), 7.80 (d, J=8.7 Hz, 2H), 7.51-7.45 (m, 3H), 7.22 (s,1H), 6.87 (dd, J=9.0 Hz and 1.8 Hz, 1H), 4.72-4.69 (m, 1H), 4.15 (q,J=6.6 Hz, 2H), 2.23-1.80 (m, 7H), 1.26 (d, J=6.0 Hz, 6H), 1.13 (t, J=7.2Hz, 3H). 761 169-173 392.1 *** (DMSO, 300 MHz) δ10.06 (s, 1H), 7.90 (d,J=8.7 Hz, 2H), 7.54-7.46 (m, 3H), 7.22 (d, J=1.5 Hz, 1H), 6.88 (dd,J=8.4 Hz and 2.1 Hz, 1H), 4.75-4.66 (m, 1H), 4.15 (q, J=7.2 Hz, 2H),4.03 (s, 2H), 3.37 (s, 3H), 1.26 (d, J=6.0 Hz, 6H), 1.16 (t, J=7.2 Hz,3H). 762 190-193 452.3 *** (DMSO, 300 MHz) δ10.20 (s, 1H), 7.78 (d,J=8.7 Hz, 2H), 7.52-7.45 (m, 3H), 7.30-7.21 (m, 5H), 7.18-7.14 (m, 1H),6.88 (dd, J=8.4 Hz and 2.1Hz, 1H), 4.73-4.69 (m, 1H), 4.15 (q, J=6.6 Hz,2H), 2.91 (t, J-7.5 Hz, 2H), 2.65 (t, J=7.6 Hz, 2H), 1.27 (d, J=6.0 Hz,6H), 1.14 (t, J=7.2 Hz, 3H). 763 209.2-209.7 424.3 *** (DMSO, 300 MHz)δ10.54 (s, 1H), 8.93-7.96 (m, 4H), 7.62-7.49 (m, 6H), 7.26 (d, J=1.8 Hz,1H), 6.91 (dd, J=8.7 Hz and 2.1 Hz, 1H), 4.76-4.72 (m, 1H), 4.21 (q,J=7.2 Hz, 2H), 1.30 (d, J=6.0 Hz, 6H), 1.18 (t, J=6.9 Hz, 3H). 764213.5-231.7 442.2 *** (DMSO, 300 MHz) δ10.52 (s, 1H), 8.06-7.96 (m, 4H),7.58 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 1H), 7.37 (t, J=8.7 Hz, 2H),7.24 (s, 1H), 6.89 (dd, J=9.0 Hz and 1.5 Hz, 1H), 4.72-4.66 (m, 1H),4.18 (q, J=7.2 Hz, 2H), 1.27 (d, J=6.0 Hz, 6H), 1.16 (t, J=6.9 Hz, 3H).765 288.5-288.9 438.2 ** (DMSO, 300 MHz) δ10.91 (s, 1H), 8.72 (s, 1H),8.20 (d, J=9.3 Hz, 1H), 8.03- 7.98 (m, 3H), 7.65-7.62 (d, J=9.0 Hz, 3H),7.08 (d, J=2.4 Hz, 1H), 6.96 (dd, J=8.7 Hz and 2.4 Hz, 1H), 4.20 (q,J=6.8 Hz, 2H), 3.81 (s, 31-1), 1.19 (t, J=7.2 Hz, 3H). 766 192.8-193.1440.1 ** (MeOD, 300 MHz) δ 7.98 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.1 Hz,2H), 7.50 (d, J=9.3 Hz, 1H), 7.11 (s, 1H), 6.99 (d, J=6.6 Hz, 1H), 6.60(s, 1H), 4.24 (q, J=7.4 Hz, 2H), 3.87 (s, 3H), 2.54 (s, 3H), 1.30 (t,J=6.9 Hz, 3H). 767 204-205 350.9 *** 768 170-175 429.4 * 769 118-123473.5 * 770 361.5 * 771 361.5 *** 772 211-212 442.4 *** ¹H NMR (300 MHz,CDCl₃): δ 7.62 (1H, d, J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz), 7.13 (2H, d,J=8.5 Hz), 6.95 (1H, dd, J=8.5, 1.8 Hz), 6.87 (1H, d, J=1.8 Hz), 5.67(1H, d, J=8.8 Hz), 4.28-4.08 (8H, m), 1.47 (3H, t, J=6.9 Hz), 1.37 (6H,td, J=7.0, 0.6 Hz), 1.34 (3H, t, J=7.3 Hz). 773 191-193 434.9 ** ¹H NMR(300 MHz, CDCl₃): δ 7.60 (1H, d, J=8.8 Hz), 7.52 (2H, d, J=8.8 Hz), 7.43(2H, d, J=8.8 Hz), 6.94 (1H, dd, J=8.8, 2.2 Hz), 6.86 (1H, d, J=2.2 Hz),4.24 (2H, q, J=7.0 Hz), 4.22-4.06 (6H, m), 1.47 (3H, t, J=7.0 Hz),1.34-1.25 (6H, m). 774 205-206 410.9 ** ¹H NMR (300 MHz, CDCl₃): δ 7.63(1H, d, J=8.8 Hz), 7.53 (2H, d, J=9.0 Hz), 7.46 (2H, d, J=9.0 Hz), 6.98(1H, br s), 6.96 (1H, dd, J=8.8, 2.0 Hz), 6.88 (1H, d, J=2.0 Hz),4.17-4.09 (4H, m), 3.71-3.61 (4H, m), 1.48 (3H, t, J=7.0 Hz), 1.34 (3H,t, J=7.1 Hz). 775 482.1 ** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (1H, d, J=8.5Hz), 7.52 (2H, d, J=9.0 Hz), 7.40 (2H, d, J=9.0 Hz), 6.97 (1H, dd,J=8.5, 2.2 Hz), 6.90 (1H, d, J=2.2 Hz), 4.48 (2H, t, J=4.7 Hz), 4.26(2H, t, J=4.7 Hz), 4.05 (2H, t, J=7.6 Hz), 3.87 (2H, t, J=6.6 Hz), 3.45(2H, t, J=6.9 Hz), 2.61 (2H, p, J=7.3 Hz), 2.13 (3H, s), 1.72 (2H, hx,J=7.3 Hz), 0.79 (3H, t, J=7.4 Hz). 776 257-258 389.5 *** ¹H NMR (300MHz, DMSO-d₆): δ 11.32 (1H, s), 7.82 (2H, d, J=8.8 Hz), 7.61 (2H, d,J=8.8 Hz), 7.50 (1H, d, J=8.8 Hz), 7.24 (1H, d, J=1.8 Hz), 6.91 (1H, dd,J=8.8, 1.8 Hz), 4.52 (2H, s), 4.18 (2H, q, J=7.0 Hz), 4.11 (2H, q, J=7.0Hz), 1.36 (3H, t, J=7.0 Hz), 1.16 (3H, t, J=7.0 Hz). 777 124-127 511.6*** ¹H NMR (300 MHz, CDCl₃): δ 7.58 (1H, d, J=8.8 Hz), 7.45 (2H, d,J=8.8 Hz), 7.39 (2H, d, J=8.8 Hz), 7.33 (1H, br s), 7.31-7.15 (5H, m),6.94 (1H, dd, J=8.8, 2.2 Hz), 6.86 (1H, d, J=2.2 Hz), 4.84 (1H, t, J=6.0Hz), 4.11 (2H, q, J=7.0 Hz), 4.08 (2H, q, J=7.3 Hz), 3.74 (3H, s), 3.18(1H, dd, J=14.0, 5.6 Hz), 3.07 (1H, dd, J=14.0, 6.4 Hz), 1.47 (3H, t,J=7.0 Hz), 1.30 (3H, t, J=7.3 Hz). 778 225-227 375.5 *** ¹H NMR (300MHz, CDCl₃): δ 7.73 (2H, d, J=8.8 Hz), 7.62 (1H, d, J=8.8 Hz), 7.52 (2H,d, J=8.8 Hz), 6.95 (1H, dd, J=8.8, 2.0 Hz), 6.88 (1H, d, J=2.0 Hz), 4.13(2H, q, J=7.0 Hz), 4.12 (2H, q, J=7.0 Hz), 4.04-3.99 (2H, m), 3.67-3.62(2H, m), 1.47 (3H, t, J=7.0 Hz), 1.34 (3H, t, J=7.0 Hz). 779 265-267389.5 *** ¹H NMR (300 MHz, DMSO-d₆): δ 8.42 (1H, s), 7.72 (2H, d, J=8.8Hz), 7.61 (2H, d, J=8.8 Hz), 7.53 (1H, d, J=8.5 Hz), 7.26 (1H, d, J=2.0Hz), 6.93 (1H, dd, J=8.5, 2.0 Hz), 4.25-4.08 (6H, m), 1.36 (3H, t, J=7.0Hz), 1.19 (3H, t, J=7.0 Hz). 780 219-220 463.6 ** ¹H NMR (300 MHz,CDCl₃): δ 7.65 (1H, d, J=8.8 Hz), 7.58 (2H, d, J=8.8 Hz), 7.48 (2H, d,J=8.8 Hz), 6.97 (1H, dd, J=8.8, 2.0 Hz), 6.88 (1H, d, J=2.0 Hz),4.18-4.08 (5H, m), 3.09 (3H, s), 3.00 (3H, s), 2.94 (3H, s), 1.53 (3H,d), 1.47 (3H, t, J=7.0 Hz), 1.34 (3H, t, J=7.0 Hz). 781 207-208 449.8*** ¹H NMR (300 MHz, CDCl₃): δ 7.64 (2H, d, J=8.8 Hz), 7.60 (4H, s),6.97 (1H, d, J=8.8, 2.0 Hz), 6.88 (1H, d, J =2.0 Hz), 4.12 (2H, q, J=7.0Hz), 4.11 (2H, q, J=7.0 Hz), 3.36 (3H, s), 3.23 (2H, s), 3.14 (3H, s),2.88 (3H, s), 1.48 (3H, t, J=7.0 Hz), 1.33 (3H, t, J=7.0 Hz). 782188-190 396.5 ** 783 201-202 410.5 * 784 245-246 410.5 ** 785 151-153423.5 ** ¹H NMR (CDC1₃, 300 MHz) δ (ppm) 1.38 (t, 3H), 3.30-3.37 (m,4H), 3.51- 3.58 (m, 4H), 4.06-4.18 (q, 2H), 7.45 (d, 1H), 7.54 (s, 1H),7.66 (d, 1H). 786 202-203 437.5 * 787 261-263 412.2 * 788 112-114453.9 * 789 154-156 398.2 *** 790 398.2 *** 791 149-152 396.5 *** 792182-185 350.5 *** 793 154-155 364.5 *** 794 149-151 378.5 *** 795183-185 378.5 *** 796 124-125 392.6 ** 797 209-212 277.9 ** 798193.4-193.7 429.2 * (CD₃CN, 400 MHz) δ9.19 (s, 1H), 7.95 (d, J=7.6 Hz,2H), 7.61 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.8 Hz, 1H), 7.10 (s, 1H), 6.92(dd, J=8.8 Hz and 0.8 Hz, 1H), 6.56 (s, 1H), 4.74-4.64 (m, 1H), 4.18 (q,J=7.2 Hz, 2H), 2.51 (s, 3H), 1.27 (d, J=6.0 Hz, 6H), 1.27 (t, J=7.2 Hz,3H). 799 362.2 *** ¹H NMR (DMSO, 300 MHz), δ 10.14 (s, 1H), 7.79 (d,J=8.4 Hz, 2H), 7.52- 7.50 (m, 3H), 7.22 (s, 1H), 6.91 (d, J=8.7 Hz, 1H),4.17 (q, J=7.5 Hz, 2H), 3.82 (s, 3H), 2.24 (t, J=7.2 Hz, 2H), 1.60 (q,J=7.2 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H). 801199-219 374.2 *** ¹H NMR (CDCl₃, 300 Hz), 7.72 (d, J=8.4 Hz, 2H), 7.63(d, J=8.7 Hz, 1H), 7.50 (d, J=8.7 Hz, 2H), 7.22 (s, 1H), 6.91 (dd, J=6.6Hz and 2.1 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.90(s, 3H), 3.24-3.18 (m, 1H), 2.46-2.25 (m, 4H), 2.06-1.97 (m, 2H), 1.33(t, J=8.1 Hz, 3H). 802 196-198 410.2 ** ¹H NMR (DMSO, 300 Hz), δ 10.45(s, 1 H), 7.80 (d, J=8.4 Hz, 2 H), 7.54-7.48 (m, 3 H), 7.33-7.21 (m,6H), 6.92 (dd, J=6.6 Hz and 2.1 Hz, 1 H) 4.17 (q, J=6.6 Hz, 2H), 3.82(s, 3 H), 3.67 (s, 2H), 1.15(t, J=7.2 Hz, 3 H). 803 216-217 386.1 * ¹HNMR (DMSO, 300 Hz), δ 10.90 (s, 1H), 8.71 (s, 1H), 8.19 (d, J=9.3 Hz,1H), 8.02-7.98 (m, 3H), 7.63 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H),7.24 (d, J=2.1 Hz, 1H), 6.92 (dd, J=6.6 Hz and 2.1 Hz, 1H), 4.20 (q,J=6.6 Hz, 2H), 3.83 (s, 3H), 1.16 (t, J=6.6 Hz, 3H). 804 214-216 401.2 *¹H NMR (DMSO, 300 Hz), δ 10.92 (s, 1H), 8.00 (d, J=8.7 Hz, 2H), 7.59 (d,J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 1H), 7.23 (d, J=2.1 Hz, 1H), 6.92 (dd,J=6.6 Hz and 2.1 Hz, IH), 6.69 (s, 1H), 4.19 (q, J=6.6 Hz, 2H), 3.83 (s,3H), 2.49 (s, 3H), 1.17 (t, J=7.2 Hz, 3H). 805 217-222 452.5 * 806157-159 422.5 ** 807 171-172 396.5 *** 808 195-197 410.5 ** 809 167-168410.5 ** 810 209-211 422.5 ** 811 166-168 354.5 * 812 206-208 460.4 **813 176-177 458.4 *** 814 164-165 [NH-] * 458.5 815 153-154 473.5 * ¹HNMR (300 MHz, CDCl₃): δ 7.65 (1H, d, J=8.8 Hz), 7.61 (2H, d, J=8.8 Hz),7.56 (2H, d, J=8.8 Hz), 6.98 (1H, dd, J=8.8, 2.3 Hz), 6.89 (1H, d, J=2.3Hz), 4.24 (2H, t, J=5.4 Hz), 4.17 (2H, q, J=7.3 Hz), 4.02 (2H, q, J=5.4Hz), 3.91 (3H, s), 3.00 (3H, s), 2.01 (3H, s), 1.38 (3H, t, J=7.3 Hz).816 186-187 445.5 ** ¹H NMR (300 MHz, CDCl₃): δ 7.66 (1H, d, J=8.5 Hz),7.60 (2H, d, J=8.8 Hz), 7.55 (2H, d, J=8.8 Hz), 6.98 (1H, dd, J=8.5, 2.0Hz), 6.89 (1H, d, J=2.0 Hz), 4.16 (2H, q, J=7.3 Hz), 3.93 (2H, t, J=6.0Hz), 3.91 (3H, s), 3.53 (2H, t, J=6.0 Hz), 3.38 (3H, s), 3.07 (3H, s),1.38 (3H, t, J=7.3 Hz). 817 188-190 439.2 * 818 158-159 437.0 *** 819438.9 * 820 408.4 ** 821 408.4 * 822 144-145 439.9 ** 823 93-94 456.2 *824 169-170 428.2 * 825 109-110 444.2 * 826 160-161 432.1 ** 827 189-191446.1 *** 828 198-200 431.2 ** ¹H NMR (300 MHz, CDCl₃): δ 7.65 (1H, d,J=8.8 Hz), 7.62 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 6.98 (1H, dd,J=8.8, 2.0 Hz), 6.89 (1H, d, J=2.0 Hz), 4.17 (2H, q, J=7.2 Hz), 3.93(2H, t, J=5.3 Hz), 3.91 (3H, s), 3.77 (2H, t, J=5.3 Hz), 3.06 (3H, s),1.38 (3H, t, J=7.2 Hz). 829 271-275 422.1 ** 830 178-179 420.1 ** 831140-141 371.0 * 832 206-207 406.3 ** ¹H NMR (CDC1₃, 300 MHz) δ (ppm)1.34 (t, 3H), 1.47 (t, 3H), 1.55 (s, 9H), 4.04-4.25 (m, 4H), 6.62 (s,1H), 6.86- 6.92 (m, 1H), 7.02-7.08 (m, 2H), 7.43- 7.49 (m, 2H), 7.62 (d,1H), 7.95 (d, 1H). 833 183-185 306.3 ** ¹H NMR (CDC1₃, 300 MHz) δ (ppm)1.21 (t, 3H), 1.37 (t, 3H), 3.84-4.09 (m, 6H), 6.54-6.71 (m, 2H),6.85-7.01 (m, 2H), 7.23-7.45 (m, 3H). 834 179-180 384.2 ** 835 178-179398.2 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm), 1.32-1.52 (m, 9H), 3.06-3.17(q, 2H), 4.07-4.24 (m 4H), 6.55 (s, 1H), 6.99- 7.10 (m, 3H), 7.42-7.50(m, 2H), 7.52- 7.53 (m, 1H), 7.69 (d, 1H). 836 167-169 412.2 * 837144-145 410.2 * 838 193-194 378.1 ** ¹H NMR (CDCl₃, 300 MHz) δ (ppm),1.31-1.39 (m, 6H), 1.48 (t, 3H), 4.07- 4.31 (m, 6H), 6.73 (s, 1H),6.88-6.95 (m, 1H), 7.01-7.08 (m, 2H), 7.42-7.53 (m, 2H), 7.63 (d, 1H),7.99 (s, 1H). 839 249-250 377.3 * ¹H NMR (CDC1₃, 300 MHz) δ (ppm), 1.13(t, 3H), 1.32 (t, 3H), 1.43 (t, 3H), 3.20-3.32 (m, 2H), 4.13-4.26 (m,4H), 5.77 (t, 1H), 7.06-7.18 (m, 3H), 7.48 (d, 1H), 7.52-7.59 (m, 2H),8.02 (s, 1H), 8.18 (d, 1H). 840 182-183 442.5 * 841 140-141 429.2 * 842170-171 427.2 * ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 1.04-1.13 (m, 2H),1.20-1.28 (m, 2H), 1.44 (t, 3H), 2.30-2.43 (m, 1H) 3.44- 3.61 (m, 8H),4.10-4.23 (q, 2H), 7.49 (d, 1H), 7.56 (s, 1H), 7.72 (d, 1H). 843 143-146463.1 * 844 220-227 378.1 * 845 210-215 435.0 * 846 201-202 391.5 ** 847166-167 405.5 ** 848 193-194 453.5 ** 849 159-161 364.5 ** 850 179-180446.4 ** 851 186-187 410.4 ** 852 171-172 426.4 ** 853 159-161 346.2 ***854 330.2 ** 855 332.1 ** 856 202-202 368.1 * 857 192-192 364.2 ** 858362.2 *** 859 191-192 374.2 ** 860 242-244 334.1 ** 861 346.2 ** 862360.1 * 863 362.5 ** 864 362.5 ** 865 187-192 412.9 *

Example 7 Evaluation of the Activity of Compounds Using anHCV-Poliovirus Chimera

In an HCV-poliovirus (HCV-PV) chimera, the PV 5′ UTR is replaced by theHCV 5′ UTR and partial (the first 123 amino acids) core coding sequences(nucleotides 18 to 710 of HCV 1b) as shown in FIG. 1 (140). As aconsequence, the expression of poliovirus proteins is proteins is underregulation of the HCV IRES. Poliovirus is a picornavirus in whichprotein translation initiation is mediated by an IRES element located inthe 5′ UTR. At the 5′ end of the HCV-PV chimeric genome, there is thecloverleaf-like RNA structure of PV, an essential cis-acting replicationsignal ending with the genome-linked protein VPg. Replication kineticsof the HCV-PV chimera matches that of the parental poliovirus (Mahoney)and can result in cytopathic effects (CPE) in cell culture. Heptazyme, aribozyme that targets the HCV IRES, was shown to be active against thechimeric virus in cell culture (76, 77).

To evaluate compounds for activity against the chimeric virus, HeLacells are seeded and incubated at 37° C. under 5% CO₂ for 24 hours. Thecells are then infected with HCV-PV at a multiplicity of infection (MOI)at 0.1 for 30 min and then treated with compound for 1 day (treatmenttime will be optimized). The activity of compounds is determined by achange in cytopathic effect, plaque assay, and/or viral RNA production(see e.g., Table 1).

Example 8 Evaluation of the Activity of Compounds Against a Wild-TypePoliovirus (WT-PV) and the Poliovirus IRES Translation Assay (WT-PV MonoLuc)

A DNA construct is prepared, termed pPVIRESmono, in which PV IRESsequences are inserted (nucleotide number 1-742) between a promoter andthe firefly luciferase (Fluc) reporter gene. A stably transfected 293 Tcell line, is established by transfection with the pPVIRESmono DNA byselecting for resistance to hygromycin. As previously described, cellsare treated with compounds for 20 hours, and activity is determined byquantifying the Fluc signal. Additionally, to evaluate compoundsactivity against wild-type poliovirus, Hela cells are seeded andincubated at 37° C. under 5% CO₂ for 24 hours. Cells are then infectedwith wild-type poliovirus at a MOI at 0.1 for 30 minutes, and thentreated with compound for one day. The activity of compounds isdetermined by changes in cytopathic effect, plaque assay, and RT-PCRusing poliovirus IRES primers and probes (see e.g., Table 2).

Furthermore, if compounds are active against the poliovirus and othervirus IRESs, then the compounds are useful for treating viral infectionby any virus containing an IRES.

TABLE 2 Compound WT-PV CPE WT-PV CPE WT-PV CPE WTPV mono luc No. (100μM) * (10 μM)* (1 μM)* IC₅₀ (μM) 4 3 2 1 0.8 5 3 2 1 9 9 3 2 2 >100 10 32 2 >100 19 3 2 1 15 24 3 2 2 1.5

Example 9 In Vitro Translation Assay

In vitro translation assays can be used to distinguish between thecompounds that act on HCV IRES RNA or cellular translation factors. Inexemplary assays, the mRNA that will direct translation is a transcribedrunoff product from the T7 RNA polymerase promoter of the pHCVIRESmonoplasmid DNA generated with Ambion RNA MegaTranscript kit (Ambion, Inc.,Austin, Tex.). In vitro translation is performed using HeLa cell lysatesusing methods known to one of skill in the art. Preliminary resultsindicate that one or more of the compounds of the present invention hassignificantly higher activity against HCV IRES regulated translationafter preincubating the compound with the HCV IRES RNA transcripts thanafter preincubating with HeLa cell lysate for 30 min at 37° C. orwithout preincubation (data not shown). This suggests that this compoundmay interact with the HCV IRES RNA in the in vitro translation assay. Todemonstrate whether the compounds selectively act on the HCV IRES, pLucis used together with cellular IRES mRNA transcripts as controls for invitro translation.

All publications and patent applications cited herein are incorporatedby reference to the same extent as if each individual publication orpatent application was specifically and individually indicated to beincorporated by reference.

Although certain embodiments have been described in detail above, thosehaving ordinary skill in the art will clearly understand that manymodifications are possible in the embodiments without departing from theteachings thereof. All such modifications are intended to be encompassedwithin the claims of the invention.

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1. A compound of Formula (I):

wherein: X is: -cyano; Y is: -aryl substituted with one or more of thefollowing: —C₁ to C₆ alkoxy, substituted with: —C₁ to C₆ alkoxy,-hydroxy, -one or more halogen substituents, -5 or 6 memberedheterocycle, optionally substituted with: —C₁ to C₆ alkyl, or -hydroxy,-amino optionally substituted with one or more C₁ to C₆ alkylsubstituents, —NR_(i)SO₂R_(x), where R_(x) is C₁ to C₆ alkyl and R_(i)is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is as definedabove, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy, —NR_(J)COR_(k),where R_(k) is: —C₁ to C₆ alkyl, -hydrogen, or -amino optionallysubstituted with one or more C₁ to C₆ alkyl substituents, and R_(j) is:-hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is as defined above,—C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy, —N═N⁺═N⁻, or —COR₁, whereR₁ is 5 or 6 membered heterocycle optionally substituted with hydroxy,-amino optionally substituted with one or more C₁ to C₆ alkylsubstituents, —C₁ to C₆ alkyl substituted with: —NHSO₂R_(x), where R_(x)is as defined above, or —NR_(x)SO₂R_(x), where R_(x), is as definedabove, —C₁ to C₆ haloalkoxy, -hydroxy, —COOR_(x), where R_(x) is asdefined above, —COR_(m), where R_(m) is: -amino optionally substitutedwith: (i) -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or (ii)one or more C₁ to C₆ alkyl substituents, where the C₁ to C₆ alkylsubstituents are optionally substituted with:  -hydroxy  -5 or 6membered heterocycle,  -amino optionally substituted with one or more C₁to C₆ alkyl substituents,  —C₁ to C₆ alkoxy, -3 to 7 memberedheterocycle, optionally substituted with C₁ to C₆ alkyl, optionallysubstituted with di-C₁ to C₆ alkyl-amino, —NHR_(n), where R_(n) is:—CH₂CONH₂, or -aryl optionally substituted with:  —C₁ to C₆ alkyl,  -oneor more halogen substituents,  -nitro, or  -one or more C₁ to C₆ alkoxysubstituents, —NR_(o),COR_(p), where R_(p) is: —C₁ to C₆ alkyloptionally substituted with: -halogen, —C₁ to C₆ alkoxy, or -aryl,-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -5 or 6 memberedheterocycle, -aryl, optionally substituted with halogen, -5 or 6membered heteroaryl optionally substituted with one or more C₁ to C₆alkyl substituents, -hydrogen,

and where R_(o) is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) isas defined above, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy,—NR_(q)CONR_(q)R_(r), where R_(q) is: -hydrogen, —C₁ to C₆ alkyl, —C₁ toC₆ haloalkyl, —C₁ to C₆ haloalkoxy, or —COR_(x), where R_(x) is asdefined above, and where R_(r) is: -aryl optionally substituted with:

—C₁ to C₆ alkyl, —C₁ to C₆ haloalkyl, —OR_(s), where R_(s) is aryl, or—COOR_(x), where R_(x) is as defined above, —C₁ to C₆ alkyl optionallysubstituted with one or more of the following: -halogen, —C₂ to C₆alkenyl, -aryl, or —COOR, where R_(x) is as defined above, —COOR_(x),where R_(x) is as defined above, -cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl, —NR_(t)COOR_(u), where R_(u) is: —C₁ to C₁₂ alkyl,optionally substituted with: -aryl optionally substituted with C₁ to C₆alkyl or C₁ to C₆ alkoxy, —C₂ to C₆ alkenyl, —C₁ to C₆ alkoxy, —C₂ to C₆alkynyl, -halogen, -5 or 6 membered heterocycle, -cyclopropyl,-cyclobutyl, -cyclopentyl, or -cyclohexyl, -aryl, optionally substitutedwith: —C₁ to C₆ alkoxy, -halogen, or —C₁ to C₆ alkyl, -5 or 6 memberedheterocycle, -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,wherein cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl areoptionally substituted with one or more C₁ to C₆ alkyl substituents, andR_(t) is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is asdefined above, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy,—NR_(v)SO₂R_(w), where R_(v) is: -hydrogen, —COR_(x), where R_(x), is asdefined above, or —C₁ to C₆ alkyl, optionally substituted with:-halogen, —COR_(x), where R_(x) is as defined above, —OCOR_(x), whereR_(x) is as defined above, -hydroxyl, or —C₁ to C₆ alkoxy, and whereR_(w) is: —C₁ to C₆ alkyl optionally substituted with: -halogen, —C₁ toC₆ haloalkyl, -aryl, or -5 or 6 membered heterocycle, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, —C₂ to C₆ alkenyl, —C₁ to C₆alkyl- or di-C₁ to C₆ alkyl-amino optionally substituted with halogen,-5 or 6 membered heterocycle, or -5 or 6 membered heteroaryl optionallysubstituted with: —C₁ to C₆ alkyl, -5 or 6 membered heterocycle, or

 optionally substituted with C₁ to C₆ alkyl, where R_(y) is C₁ to C₆alkyl or hydrogen,

where R_(x), is hydrogen or C₁ to C₆ alkyl, optionally substituted witharyl, —SR_(x), where R_(x) is as defined above, —SO₂R_(aa), where R_(aa)is: —C₁ to C₆ alkyl, -amino, —C₁ to C₆ alkyl- or di-C₁ to C₆ alkyl-aminooptionally substituted with hydroxy or —COOR_(x), where R_(x) is asdefined above, -5 or 6 membered heteroaryl, -cyclopropylamino,cyclobutylamino, cyclopentylamino, or cyclohexylamino, -aryl, or—NHR_(bb), where R_(bb) is:

—C(═S)NH₂, or —PO(OR_(x))₂, where R_(x) is as defined above; Z is:-hydrogen; —C₁ to C₆ alkyl optionally substituted with: —C₁ to C₆alkoxy, -one or more halogen substituents, or -aryl; —C₂ to C₆ alkenyl;-aryl optionally substituted with C₁ to C₆ alkoxy or one or more C₁ toC₆ alkyl substituents; —COOR_(x), where R_(x) is as defined above;

-cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl;-cyclopropylmethyl; -cyclobutylmethyl; or -cyclopentylmethyl; R ishydrogen, halogen or C₁ to C₆ alkoxy; R₁ is: -hydrogen; -hydroxy;-halogen; —C₁ to C₆ haloalkyl; -nitro; -5 or 6 membered heteroaryl; -5or 6 membered heterocycle; —C₁ to C₆ alkoxy optionally substituted with:-one or more halogen substituents, -aryl, or -5 or 6 memberedheterocycle; -aryl optionally substituted with C₁ to C₆ alkoxy;—COR_(x), where R_(x) is as defined above; —C₁ to C₆ alkyl optionallysubstituted with di-C₁ to C₆ alkyl-amino or 5 or 6 membered heterocycle;-cyclopropyl; -cyclobutyl; -cyclopentyl; or -cyclohexyl; and whereinwhen R₂ is unsubstituted methoxy, then R₁ is hydrogen; R₂ is: -nitro;-hydrogen; -halogen; -hydroxy; —C₁ to C₆ alkyl, optionally substitutedwith one or more halogen substituents; -cyclopropyl; -cyclobutyl;-cyclopentyl; -cyclohexyl; -amino; —C₁ to C₆ alkoxy optionallysubstituted with: -one or more halogen substituents, —OCOR_(X), whereR_(x) is as defined above, -di-C₁ to C₆ alkyl-amino optionallysubstituted with C₁ to C₆ alkoxy, -5 or 6 membered heterocycleoptionally substituted with C₁ to C₆ alkyl, -5 or 6 membered heteroaryl,or -aryl; —COOR_(x), where R_(x) is as defined above; —C₁ to C₆haloalkyl; -amide optionally substituted with: -hydroxy, or -aryl; -5 or6 membered heteroaryl; —OCOR_(x), where R_(x) is as defined above;—NHCOR_(jj), where R_(jj) is: —C₁ to C₆ alkoxy, or -amino optionallysubstituted with one or more C₁ to C₆ alkyl substituents; —OR_(kk),where R_(kk) is 5 to 6 membered heteroaryl; —NHSO₂R_(x), where R_(x) isas defined above; —NHSO₂cyclopropyl; —NHSO₂cyclobutyl;—NHSO₂cyclopentyl; or —NHSO₂cyclohexyl; and wherein when R₁ isunsubstituted methoxy, then R₂ is hydrogen; and R₃ is: -hydrogen; or—CH₂OCOR_(x), where R_(x) is as defined above; or a pharmaceuticallyacceptable salt thereof.
 2. A compound of Formula (I):

wherein: X is: -cyano; Y is:

Z is: -hydrogen; —C₁ to C₆ alkyl optionally substituted with: —C₁ to C₆alkoxy, -one or more halogen substituents, or -aryl; —C₂ to C₆ alkenyl;-aryl optionally substituted with C₁ to C₆ alkoxy or one or more C₁ toC₆ alkyl substituents; —COOR_(x), where R_(x) is as defined above;

-cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl;-cyclopropylmethyl; -cyclobutylmethyl; or -cyclopentylmethyl; R ishydrogen, halogen or C₁ to C₆ alkoxy; R₁ is: -hydrogen; -hydroxy;-halogen; —C₁ to C₆ haloalkyl; -nitro; -5 or 6 membered heteroaryl; -5or 6 membered heterocycle; —C₁ to C₆ alkoxy optionally substituted with:-one or more halogen substituents, -aryl, or -5 or 6 memberedheterocycle; -aryl optionally substituted with C₁ to C₆ alkoxy;—COR_(x), where R_(x) is as defined above; —C₁ to C₆ alkyl optionallysubstituted with di-C₁ to C₆ alkyl-amino or 5 or 6 membered heterocycle;-cyclopropyl; -cyclobutyl; -cyclopentyl; or -cyclohexyl; R₂ is: -nitro;-hydrogen; -halogen; -hydroxy; —C₁ to C₆ alkyl, optionally substitutedwith one or more halogen substituents; -cyclopropyl; -cyclobutyl;-cyclopentyl; -cyclohexyl; -amino; —C₁ to C₆ alkoxy optionallysubstituted with: -one or more halogen substituents, —OCOR_(X), whereR_(x) is as defined above, -di-C₁ to C₆ alkyl-amino optionallysubstituted with C₁ to C₆ alkoxy, -5 or 6 membered heterocycleoptionally substituted with C₁ to C₆ alkyl, -5 or 6 membered heteroaryl,or -aryl; —COOR_(x), where R_(x) is as defined above; —C₁ to C₆haloalkyl; -amide optionally substituted with: -hydroxy, or -aryl; -5 or6 membered heteroaryl; —OCOR_(x), where R_(x) is as defined above;—NHCOR_(jj), where R_(jj) is: —C₁ to C₆ alkoxy, or -amino optionallysubstituted with one or more C₁ to C₆ alkyl substituents; —OR_(kk),where R_(kk) is 5 to 6 membered heteroaryl; —NHSO₂R_(x), where R_(x) isas defined above; —NHSO₂cyclopropyl; —NHSO₂cyclobutyl;—NHSO₂cyclopentyl; or —NHSO₂cyclohexyl; and R₃ is: -hydrogen; or—CH₂OCOR_(x), where R_(x) is as defined above; or a pharmaceuticallyacceptable salt thereof.
 3. The compound of claim 1, wherein Z isselected from the group consisting of -cyclopropyl; -cyclobutyl;-cyclopentyl; -cyclohexyl; -cyclopropylmethyl; -cyclobutylmethyl;-cyclopentylmethyl; -hydrogen; —C₁ to C₆ alkyl optionally substitutedwith: —C₁ to C₆ alkoxy, -one or more halogen substituents, or -aryl; —C₂to C₆ alkenyl; and -aryl optionally substituted with C₁ to C₆ alkoxy. 4.The compound of claim 1, wherein R is hydrogen.
 5. The compound of claim1, wherein R₁ is selected from the group consisting of -cyclopropyl;-cyclobutyl; -cyclopentyl; -cyclohexyl; -hydrogen; -halogen; -nitro; -5or 6 membered heterocycle; —C₁ to C₆ alkoxy optionally substituted with:-aryl; -aryl optionally substituted with C₁ to C₆ alkoxy.
 6. Thecompound of claim 1, wherein R₂ is selected from the group consisting of-nitro; -hydrogen; -halogen; -hydroxy; —C₁ to C₆ alkyl, optionallysubstituted with one or more halogen substituents; -cyclopropyl;-cyclobutyl; -cyclopentyl; -cyclohexyl; —C₁ to C₆ alkoxy optionallysubstituted with: -one or more halogen substituents, —OCOR_(x), whereR_(x) is as defined above, -di-C₁ to C₆ alkyl-amino optionallysubstituted with C₁ to C₆ alkoxy, -5 or 6 membered heterocycleoptionally substituted with C₁ to C₆ alkyl, or -5 or 6 memberedheteroaryl; -amide; —NHSO₂R_(x), where R_(x) is as defined above;—NHSO₂cyclopropyl; —NHSO₂cyclobutyl; —NHSO₂cyclopentyl; or—NHSO₂cyclohexyl.
 7. The compound of claim 1, wherein R₃ is hydrogen. 8.A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition comprising a compound of claim 1 or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableexcipients.
 10. A pharmaceutical composition comprising a compound ofclaim 2 or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.
 11. A pharmaceutical compositioncomprising a compound of claim 8 or a pharmaceutically acceptable saltthereof and one or more pharmaceutically acceptable excipients.
 12. Acompound of Formula (I):

wherein: X is: -cyano; Y is: -aryl substituted with one or more of thefollowing: —C₁ to C₆ alkoxy, optionally substituted with: —C₁ to C₆alkoxy, -hydroxy, -one or more halogen substituents, -5 or 6 memberedheterocycle, optionally substituted with: —C₁ to C₆ alkyl, or -hydroxy,-amino optionally substituted with one or more C₁ to C₆ alkylsubstituents, —NR_(i)SO₂R_(x), where R_(x) is C₁ to C₆ alkyl and R_(i)is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is as definedabove, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy, —NR_(j)COR_(k),where R_(k) is: —C₁ to C₆ alkyl, -hydrogen, or -amino optionallysubstituted with one or more C₁ to C₆ alkyl substituents, and R_(j) is:-hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is as defined above,—C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy, —N═N═⁺═N⁻, or —COR₁, whereR₁ is 5 or 6 membered heterocycle optionally substituted with hydroxy,-amino optionally substituted with one or more C₁ to C₆ alkylsubstituents, -nitro, —C₁ to C₆ alkyl, optionally substituted with:—NHSO₂R_(x), where R_(x) is as defined above, or —NR_(x)SO₂R_(x), whereR_(x) is as defined above, —C₁ to C₆ haloalkoxy, -halogen, -hydroxy,—COOR_(x), where R_(x) is as defined above, —COR_(m), where R_(m) is:-amino optionally substituted with: (i) -cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, or (ii) one or more C₁ to C₆ alkylsubstituents, where the C₁ to C₆ alkyl substituents are optionallysubstituted with: -hydroxy  -5 or 6 membered heterocycle,  -aminooptionally substituted with one or more C₁ to C₆ alkyl substituents, —C₁to C₆ alkoxy, -3 to 7 membered heterocycle, optionally substituted withC₁ to C₆ alkyl, optionally substituted with di-C₁ to C₆ alkyl-amino,—NHR_(n), where R_(n) is: —CH₂CONH₂, or -aryl optionally substitutedwith: —C₁ to C₆ alkyl,  -one or more halogen substituents,  -nitro, or -one or more C ₁ to C₆ alkoxy substituents, —NR_(o)COR_(p), where R_(p)is: —C₁ to C₆ alkyl optionally substituted with: -halogen, —C₁ to C₆alkoxy, or -aryl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl,-5 or 6 membered heterocycle, -aryl, optionally substituted withhalogen, -5 or 6 membered heteroaryl optionally substituted with one ormore C₁ to C₆ alkyl substituents, -hydrogen,

and where R_(o) is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) isas defined above, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy,—NR_(q)CONR_(q)R_(r) where R_(q) is: -hydrogen, —C₁ to C₆ alkyl, —C₁ toC₆ haloalkyl, —C₁ to C₆ haloalkoxy, or —COR_(x), where R_(x) is asdefined above, and where R_(r), is: -aryl optionally substituted with:

—C₁ to C₆ alkyl, —C₁ to C₆ haloalkyl, —OR_(s), where R_(s) is aryl, or—COOR_(x), where R_(x) is as defined above, —C₁ to C₆ alkyl optionallysubstituted with one or more of the following: -halogen, —C₂ to C₆alkenyl, -aryl, or —COOR_(x), where R_(x) is as defined above,—COOR_(x), where R_(x) is as defined above, -cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, —NR_(t)COOR_(u), where R_(u), is: —C₁ to C₁₂alkyl, optionally substituted with: -aryl optionally substituted with C₁to C₆ alkyl or C₁ to C₆ alkoxy, —C₂ to C₆ alkenyl, —C₁ to C₆ alkoxy, —C₂to C₆ alkynyl, -halogen, -5 or 6 membered heterocycle, -cyclopropyl,-cyclobutyl, -cyclopentyl, or -cyclohexyl, -aryl, optionally substitutedwith: —C₁ to C₆ alkoxy, -halogen, or —C₁ to C₆ alkyl, -5 or 6 memberedheterocycle, -cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl,wherein cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl areoptionally substituted with one or more C₁ to C₆ alkyl substituents, andR_(t) is: -hydrogen, —C₁ to C₆ alkyl, —COR_(x), where R_(x) is asdefined above, —C₁ to C₆ haloalkyl, or —C₁ to C₆ haloalkoxy,—NR_(v)SO₂R_(w), where R_(v) is: -hydrogen, —COR_(x), where R_(x) is asdefined above, or —C₁ to C₆ alkyl, optionally substituted with:-halogen, —COR_(x), where R_(x) is as defined above, —OCOR_(x), whereR_(x) is as defined above, -hydroxyl, or —C₁ to C₆ alkoxy, and whereR_(w) is: —C₁ to C₆ alkyl optionally substituted with: -halogen, —C₁ toC₆ haloalkyl, -aryl, or -5 or 6 membered heterocycle, -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, —C₂ to C₆ alkenyl, —C₁ to C₆alkyl- or di-C₁ to C₆ alkyl-amino optionally substituted with halogen,-5 or 6 membered heterocycle, or -5 or 6 membered heteroaryl optionallysubstituted with: —C₁ to C₆ alkyl, -5 or 6 membered heterocycle, or

 optionally substituted with C₁ to C₆ alkyl, where R_(y) is C₁ to C₆alkyl or hydrogen,

where R_(z), is hydrogen or C₁ to C₆ alkyl, optionally substituted witharyl, —SR_(x), where R_(x) is as defined above, —SO₂R_(aa), where R_(aa)is: —C₁ to C₆ alkyl, -amino, —C₁ to C₆ alkyl- or di-C₁ to C₆ alkyl-aminooptionally substituted with hydroxy or —COOR_(x), where R_(x) is asdefined above, -5 or 6 membered heteroaryl, -cyclopropylamino,cyclobutylamino, cyclopentylamino, or cyclohexylamino, -aryl, or—NHR_(bb), where R_(bb) is:

—C(═S)NH₂, or —PO(OR_(x))₂, where R_(x) is as defined above; Z is: —C₁to C₆ alkyl optionally substituted with: —C₁ to C₆ alkoxy, -one or morehalogen substituents, or -aryl; —C₂ to C₆ alkenyl; -aryl optionallysubstituted with C₁ to C₆ alkoxy or one or more C₁ to C₆ alkylsubstituents; —COOR_(x), where R_(x) is as defined above;

-cyclopropyl; -cyclobutyl; -cyclopentyl; -cyclohexyl;-cyclopropylmethyl; -cyclobutylmethyl; or -cyclopentylmethyl; R ishydrogen, halogen or C₁ to C₆ alkoxy; R₁ is: -hydrogen; -hydroxy;-halogen; —C₁ to C₆ haloalkyl; -nitro; -5 or 6 membered heteroaryl; -5or 6 membered heterocycle; —C₁ to C₆ alkoxy optionally substituted with:-one or more halogen substituents, -aryl, or -5 or 6 memberedheterocycle; -aryl optionally substituted with C₁ to C₆ alkoxy; —COR,where R_(x) is as defined above; —C₁ to C₆ alkyl optionally substitutedwith di-C₁ to C₆ alkyl-amino or 5 or 6 membered heterocycle;-cyclopropyl; -cyclobutyl; -cyclopentyl; or -cyclohexyl; and whereinwhen R₂ is unsubstituted methoxy, then R₁ is hydrogen; R₂ is: -nitro;-hydrogen; -halogen; -hydroxy; —C₁ to C₆ alkyl, optionally substitutedwith one or more halogen substituents; -cyclopropyl; -cyclobutyl;-cyclopentyl; -cyclohexyl; -amino; —C₁ to C₆ alkoxy optionallysubstituted with: -one or more halogen substituents, —OCOR_(x), whereR_(x) is as defined above, -di-C₁ to C₆ alkyl-amino optionallysubstituted with C₁ to C₆ alkoxy, -5 or 6 membered heterocycleoptionally substituted with C₁ to C₆ alkyl, -5 or 6 membered heteroaryl,or -aryl; —COOR_(x), where R_(x) is as defined above; —C₁ to C₆haloalkyl; -amide optionally substituted with: -hydroxy, or -aryl; -5 or6 membered heteroaryl; —OCOR_(x), where R_(x) is as defined above;—NHCOR_(jj), where R_(jj) is: —C₁ to C₆ alkoxy, or -amino optionallysubstituted with one or more C₁ to C₆ alkyl substituents; —OR_(kk),where R_(kk) is 5 to 6 membered heteroaryl; —NHSO₂R_(x), where R_(x) isas defined above; —NHSO₂cyclopropyl; —NHSO₂cyclobutyl;—NHSO₂cyclopentyl; or —NHSO₂cyclohexyl; and wherein when R₁ isunsubstituted methoxy, then R₂ is hydrogen; and R₃ is: -hydrogen; or—CH₂OCOR_(x), where R_(x) is as defined above; or a pharmaceuticallyacceptable salt thereof.
 13. The compound of claim 12, wherein Y is:-aryl substituted with one or more of the following: —C₁ to C₆ alkoxy-nitro, —C₁ to C₆ alkyl -halogen; and Z is: —C₁ to C₆ alkyl optionallysubstituted with: —C₁ to C₆ alkoxy, -one or more halogen substituents,or -aryl.
 14. A pharmaceutical composition comprising a compound ofclaim 12 or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.